Final-for-publication-Migraine-6-Treatment-principles-NT-clean.pptx

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1. Migraine Treatment principles

2. Migraine Historical context for migraine treatment Migraine has been described by physicians through the last two millennia, with some paying greater attention to symptoms other than headache 1 . Historically, ‘surgical’ procedures included trepanning (drilling a hole in the skull), scalp incisions, application of heated irons, and blood letting 1,2 . In the less-distant past, treatments have included several chemicals, including trinitrine ( nitroglycerin ), which is now known to be a vasoactive substance 1 . In modern times, various analgesics are used in the treatment of migraine attacks, and a wide range of therapies specifically targeted at treating migraine have been developed. Today, migraine treatment is often considered as either aimed at 3,5 : reducing or eliminating the pain and other symptoms associated with an attack ( acute treatment ) reducing the frequency, severity, disability and duration of attacks ( preventive treatment ) CGRP=calcitonin gene-related peptide; NSAID=non-steroidal anti-inflammatory drug 1. Pearce. J Neurol Neurosurg Psychiatry 1986;49(10):1097–1103; 2. Koehler & Boes. Brain 2010;133:2489–2500; 3. Martelletti & Giamberardino. Expert Opin Pharmacother 2019;20(2):209–218;4. Marmura et al. Headache 2015;55(1):3–20; 5. Silberstein. Neurology 2000;55(6):754–762; 6. Worthington et al. Can J Neurol Sci 2013;40(5 Suppl 3):S1–S80

3. Migraine treatment and management Migraine

4. Updates and variations Guidelines are continuously updated when new treatments and evidence arise. Many countries will have national guidelines that are tailored to the specific healthcare system. There is overlap between the various recommendations for treatment of migraine, but also considerable differences. Migraine Clinical treatment guidelines There is no universal treatment guideline for the treatment of migraine – various evidence-based treatment guidelines and consensus statements have been developed to aid clinicians and improve care. What are clinical treatment guidelines? Guidelines aim to improve the quality of care by making expert recommendations easily available for clinicians. Guidelines aggregate the best available empirical evidence for existing treatments and provide weighted recommendations based on the quality of the evidence while taking clinical applicability and patient perspectives into account 1,2 . When evidence is weak or lacking, expert testimonies are often used to provide consensus recommendations 1 . NICE National Institute for Health and Care Excellence website: Developing NICE guidelines: the manual. Accessed September 2022 Murad MH. Mayo Clin Proc. 2017: 92(3):423-433.

5. Migraine European recommendations for treatment and management of migraine in adults 1 Adapted from Eigenbrodt et al. Nat Rev Neurol. 2021 Eigenbrodt et al. Nat Rev Neurol. 2021 ICHD-3 International Classification of Headache Disorders, third edition Before treatment Treatment Clinical management and follow-up 1. Suspect migraine when patients experience: Recurrent headache, often unilateral/ pusating Accompanying symptoms, e.g. nausia Transient focal neurological symptoms (aura), often visual Symptom onset around puberty Family history of migraine 2. Diagnosis Take careful medical history and use diagnostic criteria (e.g., ICHD-3 2 ). Use validated diagnostic aids and screening instruments. Consider differential diagnosis. 3. Patient centricity Provide appropriate reassurance, explanation, and agree on realistic objectives Educate patients on the disease and the principles of management Consider trigger factors and use stepped care 4. Acute : Offer acute medication following guidelines and advise that Medication should be used early in the attack Frequent repeated use of acute medication risks development of Medication Overuse Headache (MOH) 5. Preventive : Offer preventive treatment for patients who are adversely affected by migraine ≥2 days per month despite optimal acute treatment. 6. Special populations : For older people, children and adolescents, pregnant or breastfeeding women, and women with menstrual migraine special guidelines may apply 7. Evaluate treatment Evaluate treatment shortly after initiation and regularly adjust thereafter Consider referral to specialist care if diagnostically challenging or difficult to treat 8. Manage complications and discourage medication overuse Educate patients about the risk of MOH and manage established MOH Recognize and modify risk factors for transition of episodic to chronic migraine, and refer to specialist care if transition to chronic migraine If MOH is ruled out, initiate preventive medication 9. Comorbidities Recognize and manage comorbidities 10. Long-term management Plan long-term follow-up and repatriate from specialist to primary care with a comprehensive treatment plan.

6. Short-term pain relief Rebound headache Higher medication dose Migraine Medication overuse ICHD-3 thresholds for overuse: regular intake of ≥1 opioid or triptan on ≥10 days/month for >3 months, or regular intake of acetaminophen or ≥1 NSAID on ≥15 days/month for >3 months 2 ICHD-3=International Classification of Headache Disorders, 3 rd edition; NSAID=non-steroidal anti-inflammatory drug Adapted from: 1. Da Silva & Lake . Headache 2014;54(1):211–217; 2. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211 Medication Headache Pain relief Successful acute treatment of migraine involves treatment and resolution of the migraine attack and symptoms Medication-overuse headache can occur with several classes of migraine therapy, including acetaminophen, caffeine combinations, opioids, barbiturates, NSAIDs, and triptans The vicious cycle of medication overuse 1

7. Migraine Treatment of migraine in young people Headaches and migraine can be very common in children and adolescents – approximately 10% of children experience migraine, and migraine is estimated to account for 75% of headaches experienced by children referred to a neurologist 1,2 . Paediatric migraine can have a considerable burden on the child, including causing lost school days, and withdrawal from social activities 1 . Treatment of paediatric migraine should be multi-focused, and include acute therapy, preventative therapy, and behavioural interventions, as well as considering patient factors such as comorbidities and development 1 . The AAN/AHS guidelines for the treatment of migraine in children recommend the use of analgesics, as well as triptans, and highlight the importance of 3 : Early treatment Choosing the correct route of administration Counselling on lifestyle factors AAN=American Academy of Neurology; AHS=American Headache Society 1. Hershey. Lancet Neurol 2010;9(2):190–204; 2. Teleanu. Maedica (Buchar) 2016;11(2):136–143; 3. Oskoui et al. Neurology 2019;93(11):487–499

8. Pharmacological treatment of acute migraine Migraine

9. Migraine Strategies for acute treatment of migraine in adults – stepped and stratified care a At dose prescribed in country, plus antiemetic; MIDAS=Migraine Disability Assessment Scale; RCT=randomised controlled trial Adapted from: Lipton et al. JAMA 2000;284(20):2599–2605 1. Ailani J et al. Headache. 2021; 61:1021-1039. 2. Ashina M et al. Lancet 2021; 397:1505-18. Non-specific analgesic a All patients Triptan therapy Response Non-response Non-specific analgesic a MIDAS grade II Triptan therapy MIDAS grades III–IV Stepped care Stratified care There are regional differences in whether stepped or stratified care is preferred. Generally , guidelines and consensus statements underline the importance of adjusting the care to meet the needs of the individual patient , taking migraine characteristics, medical history, patient preference etc. into account . 1,2 Either within same attack or across ≥ 3 consec. attacks

10. Migraine Acute pharmacological treatment of migraine For other medications there is not consensus across guidelines for their use. Evidence for efficacy should for all treatments always be balanced with: 1-3 Potential adverse events, such as peptic ulcers, risk of dependencies, tolerance and risk of medication overuse headache Patient-specific contraindications to use of a particular medication Drug–drug interactions Specific medications within the following classes are considered ‘effective’ by both the American Headache Society and the European Headache Federation: 1-3 NSAIDs Triptans Ditans Gepants NSAID=non-steroidal anti-inflammatory drug 1. Ailani, Burch, & Robbins. Headache 2021; 61: 1021-1039.; 2. Silberstein. Neurology 2000;55(6):754–762; 3. Eigenbrodt et al. Nat Rev Neurol. 2021; 17 (8): 501-514.

11. Migraine Analgesics NSAIDs are recommended for the acute treatment of migraine by many guidelines 1-3 . NSAIDs have anti-inflammatory, analgesic, and anti-pyretic proprieties, mediated by blockade of the COX enzymes, and subsequent inhibition of prostaglandin synthesis 4,5 . Several over-the-counter NSAIDs have demonstrated efficacy in treating headache and migraine 4,6 . A meta-analysis of data from 4 RCTs comparing a certain NSAID with placebo showed the NSAID to be superior 7 A double-blind study of 660 patients with migraine showed that another specific different NSAID was superior to placebo 8 . A Cochrane analysis of a different NSAID, including 1,356 patients, concluded that use of the NSAID reduced moderate-to-severe pain to no more than mild pain in 55% of those treated 9 . Other analgesics than NSAIDs are also often recommended, typically if NSAIDs are contraindicated 1,2,10 . Some over-the-counter analgesics – such as acetaminophen and acetylsalicylic acid – have shown efficacy in treating acute headache 6 . A Cochrane systematic review including 2,942 participants 9 found that acetaminophen was superior to placebo on all outcomes 9 . Another Cochrane analysis of acetylsalicylic acid data found 52% of patients treated with acetylsalicylic acid experienced pain relief at 2 hours, compared with 32% of those taking placebo 11 . COX=cyclooxygenase; NSAID=non-steroidal anti-inflammatory drug; RCT=randomised controlled trial 1. Marmura et al. Headache 2015;55(1):3–20; 2. Worthington et al. Can J Neurol Sci 2013;40(5 Suppl 3):S1–S80; 3. Eigenbrodt et al. Nat Rev Neurol. 2021; 17(8): 501-514; 4. Pardutz & Schoenen . Pharmaceuticals (Basel) 2010;3(6):1966–1987; 5. Chandrasekharan et al. Proc Natl Acad Sci USA 2002;99(21):13926–13931; 6. Vargas. Continuum ( Minneap Minn ) 2018;24(4, headache):1032–1051; 7. Suthisisang et al. Headache 2010; 50(5): 808-818; 8. Codispoti et al. Headache 2001; 41(7):665-679; 9. Derry et al. Cochrane Database Syst Rev 2013;(4):CD008783; 10. Steiner et al. J. Headache Pain 2019; 20(1):57; 11. Kirthi et al. Cochrane Database Syst Rev 2013;(4):CD008041 Non-steroidal anti-inflammatory drugs (NSAIDs) Other analgesics

12. Migraine Triptan therapy Triptans are recommended for the acute treatment of migraine for patients for whom over-the counter analgesics do not adequately relieve pain 1-3 . Triptans are agonists at 5-HT 1B and 5-HT 1D receptors, decreasing trigeminal neuron activity, and causing 4 : Vasoconstriction of cerebral blood vessels Inhibition of vasoactive peptide release by trigeminal neurons Inhibition of nociception The 5-HT 1 receptor class contains five human subtypes 5-HT 1A,B,D,E,F . Some 5-HT 1 receptor subtypes are localised to regions of the brain that are important in migraine physiology, including the meningeal blood vessels, as well as on trigeminal neurons 4 . As a class, the triptans have largely replaced the ergot alkaloids, due to a better side effect profile 5 . 5-HT=5-hydroxytryptamine (serotonin) 1. Marmura et al. Headache 2015;55(1):3–20; 2. Worthington et al. Can J Neurol Sci 2013;40(5 Suppl 3):S1–S80; 3. Eigenbrodt et al. Nat Rev Neurol. 2021; 17(8): 501-514; 4. Tepper et al. Arch Neurol 2002;59(7):1084–1088; 5. Antonaci et al. Springerplus 2016;5:637;

13. Migraine Efficacy of triptan therapy Meta-analyses and multiple-treatment comparisons have found triptan therapy to be efficacious in the treatment of migraine 1,2 . A meta-analysis of 133 RCTs of triptan therapy found that patients treated with triptans experienced: 1 Pain relief within 2 hours: 42–76% Pain freedom at 2 hours: 18–50% Sustained 24-hour pain relief: 29–50% Sustained pain freedom: 18–33% A multiple-treatment comparison, including 74 RCTs, found differences between different triptan therapies 2 . The most effective triptans provided 24-hour sustained pain relief, and 24-hour sustained headache response, whereas other triptans did not maintain their efficacy at 24 hours 2. Because of their powerful vasoconstrictor effects, the triptans as a class are used cautiously in patients with cardiovascular pathologies 3,4 . Triptans are contraindicated in patients with 3 : Arterial hypertension, Coronary heart disease, Raynaud’s disease, History of ischaemic stroke, Pregnancy and lactation. RCT=randomised controlled trial 1. Cameron et al. Headache 2015;55( Suppl 4):221–235; 2. Thorlund et al. Cephalalgia 2014;34(4):258–267; 3. González-Hernández et al. Expert Opin Drug Metab Toxicol 2018;14(1):25–41; 4. Dodick et al. Headache 2004;44(5):414–425 Patients (%) Patients experiencing pain relief within 2 hours of administration of triptan therapy – meta-analysis of 133 RCTs 1 Pain relief within 2 hours

14. Migraine Ditans When triptans are contraindicated or when response is inadequate, ditans are recommended for the acute treatment of migraine by AHS and in a guideline endorsed by EAN 1,2 . Availability varies dependent on local approvals. Ditans – are agonists at the 5-HT 1F receptor 3 . The 5-HT 1F receptor is localised to the trigeminal nerves 4 . Activation of the 5-HT 1F receptor does not appear to be as vasoconstrictive as activation of 5-HT 1B/1D receptors by triptans 4 . One 5-HT 1F agonist has been shown to be clinically effective in the treatment of migraine adult patients with or without aura 5 , and has been approved by the FDA in 2019 6 . An analysis of pooled data from 2 RCTs showed no difference between placebo and one 5-HT 1F agonist in the incidence of cardiovascular adverse events 7 . AHS=American Headache Society; EAN= European Academy of Neurology ; 5-HT=5-hydroxytryptamine (serotonin); RCT=randomised controlled trial 1. American Headache Society. Headache 2019;59(1):1–18; 2. Eigenbrodt et al. Nat Rev Neurol. 2021; 17(8): 501-514. 3.Xavier et al. Curr Clin Pharmacol 2017;12(1):36–40; 4. Do et al. J Headache Pain 2019;20(1):37; 5. Kuca et al. Neurology 2018;91:e2222–e2232; 6. FDA. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211280Orig1s000SumR.pdf Accessed 2022; 7. Shapiro et al. J Headache Pain 2019;20(1):90

15. Gepants Gepants have been approved for acute treatment of migraine (first approval by FDA 1 in 2019 and EMA 2 in 2022). Some gepants has been approved for preventive treatment of migraine (by FDA 3 in 2021 and EMA 2 in 2022). Like ditans , gepants are recommended for the acute treatment of migraine by AHS and in a guideline endorsed by EAN, when triptans are contraindicated or when response is inadequate 4,5 . Availability varies dependent on local approvals. Gepants are small-molecule CGRP receptor antagonists. The first generation of gepants showed significant reductions of headache pain and migraine associated symptoms 6 . However, developments were halted as evidence of liver toxicity associated with long-term use emerged 6,7 . This has been overcome in the currently approved second generation. 1. FDA, Approved Drugs, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211765Orig1s000SumR.pdf . Accessed Sept 2022; 2. EMA, Medicines, https://www.ema.europa.eu/en/medicines/human/EPAR/vydura Accessed Oct 2022; 3. FDA. Approved Drugs. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/215206Orig1s000IntegratedR.pdf ; 4. American Headache Society. Headache 2019;59(1):1–18; 5. Eigenbrodt et al. Nat Rev Neurol. 2021; 17(8): 501-514. 6 Edvinsson et al. Nat Rev Neurol , 2018;14(6):338–350; 7 Ashina et al. Lancet; 2021; 397:1505-18

16. Migraine Adjunct treatment - Antiemetics (anti-nausea agents) Nausea can be a distressing symptom of migraine, and one that is feared by patients 1 . There are many different antiemetic agents, with various mechanisms of action, that can reduce the feeling of nausea in some patients 1,2 . A Cochrane analysis found that a certain antiemetic drug improved the relief of migraine-related nausea and vomiting when combined with analgesic medication 3 . Furthermore, there is some evidence that combining a certain antiemetic agent with triptan therapy improves the efficacy of the triptan, although more research is needed 4,5 . In general, certain antiemetic therapies are often recommended as part of combination therapy for patients experiencing severe nausea related to migraine attacks 5,6 . 5-HT=5-hydroxytryptamine (serotonin) 1. Lyons & Ballisat . Update Anaesthesia 2016;31:38–42; 2. Hauser et al. Antiemetic Medications. 2020; 3. Kirthi et al. Cochrane Database Syst Rev 2013;(4):CD008041; 4. Schulman & Dermott. Headache 2003;43(7):729–733; 5. Worthington et al. Can J Neurol Sci 2013;40(5 Suppl 3):S1–S80; 6. Marmura et al. Headache 2015;55(1):3–20

17. Migraine Other pharmacological treatments A source of some controversy, certain opioids are recommended in some guidelines, e.g. by the American Headache Society 4 , but advised against in others, e.g. by Canadian Headache Society and European Headache Federation 1,5 Opioids are perceived as abusable drugs, and opioid overuse has been linked to worsening of patient outcomes, and to medication-overuse headache 6 Furthermore, because indiscriminate activation of the opioid signalling system can have widespread effects in the body, opioid analgesics have been linked to adverse events such as hyperalgesia and allodynia, and worsening of nausea in some patients 1,7 The ergot alkaloids are older compounds, and as such there are relatively few high-quality clinical studies investigating their efficacy in migraine compared with more modern therapies 1 RCTs have compared specific ergot alkaloids with triptan therapy in patients with migraine, showing the ergot alkaloid to be inferior to triptan therapy on the outcome of headache relief at 2 hours 2,3 Because the ergot alkaloids are vasoconstrictive, they are contraindicated in patients with cardiovascular disease, 1 coronary heart disease, cerebrovascular disease or uncontrolled hypertension 4 The European Headache Federation recommend to avoid the routine use of ergot alkaloids because of the existence of more effective treatments with better risk profiles 5 . However, outside Europe, ergot alkaloids are used as an alternative to triptans eg . 4 . RCT=randomised controlled trial 1. Worthington et al. Can J Neurol Sci 2013;40(5 Suppl 3):S1–S80; 2. Diener et al. Eur Neurol 2002;47(2):99–107; 3. The Multinational Oral Sumatriptan and Caferget Comparative Study Group. Eur Neurol 1991;31:314–322; 4. American Headache Society. Headache 2019; 59 5 . Steiner TJ, Jensen R, Katsarava Z et al. J Headache Pain 2019; 20:57. (1): 1–18; 6. Headache Classification Committee of the International Headache Society (IHS). Cephalalgia 2018;38(1):1–211; 7. DaSilva et al. Curr Pain Headache Rep 2014;18(7):429. Ergot Alkaloids Opioids

18. Preventive drug treatment of migraine Migraine

19. Migraine Criteria for preventative migraine treatment AHS consensus 1 : Headache days per month Degree of disability a Prevention should be offered ≥6 None ≥4 Some ≥3 Severe Prevention should be considered 4–5 None 3 Some 2 Moderate a As measured by scores on MIDAS (Migraine Disability Assessment Scale) 1. Adapted from: American Headache Society. Headache 2019;59(1):1–18; 2. Steiner TJ et al. J Headache Pain 2019; 20(1):57 The American Headache Society (AHS) recommends offering or considering preventive treatment based on the number of headache days per month and the degree of disability caused by the attacks 1 . The European Headache Federation (EHF) recommends offering preventive migraine treatment for any patient with migraine who is not well controlled with acute therapy alone 2 . EHF: Indications for migraine prophylaxis 2 : Migraine impairs quality of life and Migraine impairs quality of life and Attacks cause disability on ≥2 days per month Risk of over-frequent use of acute therapy and OR and Optimized acute therapy does not prevent the above Patient is willing to take daily medication

20. Migraine Antiepileptics and beta-blockers Medications used for the prevention of migraine attacks with proven high efficacy, and a mild-to-moderate adverse-event profile, include some antiepileptics, and some beta-blockers 1-3 Antiepileptics A Cochrane review of an antiepileptic in the preventative treatment of migraine found that patients treated with the antiepileptic had a reduction of approximately 4 headaches per month, compared with placebo 4 Guidelines recommend several different antiepileptics as preventative treatment for migraine 2,3 Beta-blockers A systematic review of beta-blockers in the preventative treatment of migraine found that treatment with a competitive antagonist of beta-1-adrenergic receptors reduced headache attacks by 1.5 attacks per month, compared with placebo 5 Guidelines recommend several different beta-blockers as preventative treatment for migraine 2,3 Silberstein. Neurology 2000;55(6):754–762; 2. Silberstein et al. Neurology 2012;78:1337–1345; 3. American Headache Society. Headache 2019;59(1):1–18; 4. Linde et al. Cochrane Database Syst Rev 2013;6:CD010611; 5. Jackson et al. PLoS One 2019;14(3):e0212785

21. Migraine CGRP as a new, therapeutic target in patients with migraine So-called ‘ gepants ’ are small molecules that are antagonists at CGRP receptors 7 . The gepants show good efficacy in acute treatment of migraine 7 . Monoclonal anti-CGRP antibodies have been developed that either target the CGRP protein, or the CGRP receptor 7 . Anti-CGRP antibodies and certain gepants are effective as preventative treatment for migraine, reducing the occurrence of migraine attacks 7,8 . CGRP is a 37-amino acid peptide, found throughout the body, that functions as a vasodilator 1,2 . Several lines of evidence suggest that CGRP plays a crucial role in migraine: 2 CGRP levels increase during a migraine attack 3 . Elevated CGRP levels during a migraine attack are normalised with triptan therapy 4 . IV infusion of CGRP can induce a migraine-like attack 5 . Drugs that inhibit CGRP activity are effective in treating migraine 6 . CGRP=calcitonin gene-related peptide; IV=intravenous 1. Russell et al. Physiol Rev 2014;94(4):1099–1142; 2. CGRP Forum. A background to CGRP and its receptor; 3. Goadsby et al. Ann Neurol 1990;28(2):183–187; 4. Karsan & Goadsby. Curr Neurol Neurosci Rep 2015;15(5):25; 5. Guo et al. Cephalalgia 2017;37 (2):114–124; 6. Holland & Goadsby. Neurotherapeutics 2018;15(2):304–312; 7. Deen et al. J Headache Pain 2017;18(1):96; 8. Dos Santos JBR, da Silva MRR. Eur J Pharmacol. 2022; 922:174902.

22. Migraine Anti-CGRP treatment in preventing migraine Anti-CGRP antibody treatment A systematic review of RCTs of anti-CGRP antibody therapy analysed 11 studies, which involved 4,402 patients with migraine, found that treatment was superior to placebo on several endpoints 1 . A review by the EHF recommend anti-CGRP antibody therapy in patients with episodic or chronic migraine who have not responded to at least 2 medical treatments, or who cannot use other preventative treatments because of comorbidities, side effects, or poor compliance 2 . However, further evidence of efficacy, including real-world data, is needed, as well as future biomarker research to enable identification of patients likely to respond 2 . CGRP-receptor antagonists ( gepants ) Some gepants have recently been approved for preventive treatment 3-5 . A phase III trial involving 873 patients treated preventively for 12 weeks with one gepant , found that treatment was superior to placebo in reducing the number of monthly migraine days 6 . A review of phase-1/2/3 clinical trials investigating preventive treatment with Gepants included 16 studies of which eight had been completed by January 2022. The review concluded that the investigated gepants were efficacious, safe and well-tolerated 7 . However, further evidence of the long-term efficacy and safety is needed 7 . CI=confidence interval; CGRP=calcitonin gene-related peptide; EHF=European Headache Federation; FDA=US Food and Drug Administration 1. Deng et al. BMC Neurol 2020;20(1):57; 2. Sacco et al. J Headache Pain 2019;20(1):6; 3. FDA. Drugs@FDA https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215206Orig1s000lbl.pdf. (Accessed 21 September 2022). 4. FDA. Drugs@FDA : https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212728s012lbl.pdf . (Accessed 21 September 2022); 5. EMA, Medicines, https://www.ema.europa.eu/en/medicines/human/EPAR/vydura Accessed Oct 2022 ; 6. Ailani et al. N Engl J Med. 2021;385(8):695-706; 7. Dos Santos & Da Silva. Eur J Pharmacol . 2022; 922(2022): 174902.

23. Migraine Pharmacological targets for CGRP inhibition CGRP=calcitonin gene-related peptide Adapted from: Levin et al. Headache 2018;58(10):1689–1696 Pain transmission Blood flow in cerebral blood vessels CGRP CGRP receptor Trigeminal Neuron 2 nd order neuron CGRP Trigeminal neuron Smooth muscle cells Cerebral artery CGRP Trigeminal neuron Smooth muscle cells Meningeal blood Vessel Neurogenic inflammation Mast cell Inflammatory regulators

24. Migraine Anti-CGRP therapies and their mechanism of action Various clinical data demonstrate the crucial role CGRP plays in migraine pathology, and there are several different methods of blocking CGRP activity to treat migraine attacks 1,2 . Gepants – CGRP receptor antagonists, which bind to the CGRP receptor and prevent signalling. Anti-CGRP antibodies, which prevent CGRP interacting with its receptor. Anti-CGRP receptor antibodies, which bind to the CGRP receptor and prevent signalling. Mechanism of action of anti-CGRP therapies 1 CGRP=calcitonin gene-related peptide 1. Edvinsson et al. Nat Rev Neurol 2018;14(6):338–350; 2. Dubowchik et al. J Med Chem 2020;doi:10.1021/acs.jmedchem.9b01810 CGRP Trigeminal neuron Smooth muscle cell Cerebral artery 2. Anti-CGRP antibody 3. Anti-CGRP receptor antibody No signal No signal Vasodilation 1. Gepants

25. 2016 2014 2010 Overview of all clinical trials of gepants to date indicates efficacy in acute migraine with no cardiovascular or other serious adverse effects 2018 Migraine Timeline of CGRP research CALCRL=calcitonin receptor-like receptor; CGRP=calcitonin gene-related peptide; EMA=European Medicines Agency; FDA=US Food and Drug Administration; IV=intravenous; RAMP1=receptor activity-modifying protein 1; RCP=receptor coupling protein Adapted from: Edvinsson et al. Nat Rev Neurol 2018;14(6):338–350 European Medicines Agency: Medicines: . https://www.ema.europa.eu/en/medicines/human/EPAR/aimovig Accessed 21 Sept. 2022 FDA Drugs@FDA : FDA-approved drugs: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761077Orig1s000Approv.pdf Accessed 21 Sept 2022 FDA Drugs@FDA : FDA-approved drugs: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211765Orig1s000Approv.pdf Accessed 21 Sept 2022 1982 Discovery of CGRP CGRP antibodies made to measure and localise CGRP in the trigeminal–cerebrovascular system, where it was found to be a potent vasodilator 1984 1985 CGRP first proposed to play a role in migraine 1986 Discovery of the trigeminovascular reflex: a physiological role for CGRP Presence of CGRP confirmed in human cerebral vasculature; high levels in children, decreased levels with age 1987 1990 First demonstration in patients that CGRP is released during an acute migraine attack 1993 1988 First measurement of CGRP released by trigeminal stimulation in humans Triptan shown to normalise CGRP levels during acute migraine attack in parallel with relief of headache symptoms 1998 1994 Demonstration that CGRP release by trigeminal activation is inhibited by triptans Characterisation of the multicomponent CGRP receptor that consists of CALCRL, RAMP1 and RCP 2000 Characterisation of the gepants 2002 Infusion of CGRP shown to trigger migraine attack in patients prone to migraine 2004 2005 2006 Clinical trials begin to test telcagepant and other gepants in acute migraine Merck files patent for use of CGRP antibodies for migraine treatment CGRP antibodies shown to block CGRP responses in vitro and in vivo IV CGRP receptor blocker shown to alleviate headache during a migraine 2011 2007 Clinical trials begin to evaluate use of anti-CGRP antibodies for prophylaxis of frequent and chronic migraine 2017 First CGRP a ntibody migraine therapies approved by EMA 1 and FDA 2 Phase III trials of several anti-CGRP antibodies produce positive results for migraine prevention IV anti-CGRP antibody shown to be effective for prevention of episodic migraine (Phase II trial) Anti-CGRP antibody shown to be effective in episodic migraine without serious adverse effects (Phase II trial) Several anti-CGRP antibodies and a gepant shown to be effective in Phase IIb trials Experimental Laboratory Clinical Therapy Merck halts development of telcagepant owing to liver toxicity: elevated liver enzymes after 3-month treatment for migraine prophylaxis 2015 2013 2019 First gepants approved by FDA 3

26. Non-pharmacological migraine treatment Migraine

27. Migraine Non-pharmacological approaches A number of non-pharmacologcal therapies have been developed for migraine treatment 1,2 . For example: Single-pulse transcranial magnetic stimulation Electrical trigeminal nerve stimulation Noninvasive vagus nerve stimulation Behavioural therapies Non-pharmacological therapies might be particularly relevant for patients who 1 : Prefer non-pharmacological interventions Do not respond well to specific pharmacological treatments Are pregnant Pharmacological treatment is contraindicated American Headache Society. Headache 2019;59(1):1–18; 2. Steiner TJ et al. J Headache Pain 2019; 20(1):57 Non-parmacological therapies can be used alone or in conjunction with pharmacological treatment 1 .

28. Migraine Psychological therapies Several psychological therapies may be used in patients with migraine: 1 CBT is used and effective in stress management, and in sleep disorder – stress and sleep problems are seen as important triggers for migraine BFT and relaxation training are also widely accepted therapies used in the treatment of migraine Guidelines on behavioural and physical treatment for migraine from the US Headache Consortium, published in 2000, recommend several psychological therapies, based on a review of clinical evidence (although the use of placebo or sham controls was inconsistent): 2 Relaxation training – 10 studies showing an average 32% improvement in headache index or frequency CBT – 7 studies showing an average 49% improvement in headache symptoms Thermal BFT – 5 studies showing an average 37% improvement in headache symptoms Electromyographic BFT – 5 studies showing an average 40% improvement in headache index A Cochrane review of psychological therapies identified 21 different studies of psychological interventions for migraine, but found only low-quality evidence that any of these therapies reduced migraine symptoms. The review concludes that there is a need for funding of high-quality studies of psychological therapy for migraine 3 . BFT=biofeedback therapy; CBT=cognitive behavioural therapy 1. Lee et al. J Headache Pain 2019;20(1):17; 2. Campbell et al. Evidenced-Based Guidelines for Migraine Headache: Behavioral and Physical Treatments. 2000; 3. Sharpe et al. Cochrane Database Syst Rev 2019;7:CD012295

29. Migraine management – current issues Migraine

30. Migraine Unmet needs in the treatment of migraine Many unmet needs still exist in the treatment of migraine: 1-4 Underdiagnosis and undertreatment Disabilities relating to headache and other migraine symptoms Lack of concordance between guidelines Lack of optimisation, and poor satisfaction, of current therapies Overuse, or abuse, of acute medications Poor long-term adherence Comorbidities that restrict treatment choice, including cardiovascular complications An analysis of the 2017 MAST study (i.e., before the approval of the new medical treatments for migraine), in which 15,133 patients were questioned about their migraine symptoms and treatment, revealed several unmet needs in the treatment of migraine: 5 Difficult symptoms: a 89.5% Inadequate treatment response: 74.1% Moderate-to-severe disability: 55.6% Headache recurrence within 24 hours: 38.0% Nearly all respondents to the survey reported at least 1 unmet need 5 a Including a rapid onset of attack, and headache associated with sleep; MAST=Migraine in America Symptoms and Treatment 1. CGRP Forum. Unmet needs in migraine prevention. https://www.cgrpforum.org/about-cgrp/unmet-needs-in-migraine-prevention. Accessed Apr 2020; 2. Lipton. J Fam Pract 2020;69(1 Suppl ):S1–S7; 3. Lipton et al. Headache 2013;53(8):1300–1311; 4. Buse et al. Cephalalgia 2019;39( Suppl 1):184–185, IHC-PO-121; 5. Lipton et al. Headache 2019;59(8):1310–1323

31. Migraine Satisfaction with treatment and adherence to guidelines A survey from 2007 of 183 patients with migraine questioned respondents about their satisfaction with their current migraine therapy 1 Although 58% were satisfied with the degree of pain relief, there were high levels of dissatisfaction reported with specific aspects of the current therapy 1 : A survey from 2022 in Denmark revealed that even in a country where headache care is free of cost and there is access to several inexpensive triptans, adherence to guidelines and use of migraine specific treatment is low 2 . 1.: Bigal et al. Headache 2007;47(4):475–479 2. Olesen et al. Sci Rep. 2022; 12(1):8487 Dissatisfaction with need for a 2 nd dose (42% of patients ) Dissatisfaction with recurrence of pain (50% of patients ) Dissatisfaction with speed of effect (37% of patients )

32. Migraine The under-prescription of preventative treatment In the AMPP survey from 2004 (prior to the new preventive treatments), responses were collected from 77,879 households who reported details about migraine symptoms and treatment. 11,7% of the responders met the ICDH-2 criteria for migraine. Of those, 49% treated their attacks with over-the-counter agents, whilst 20% used prescription medication 1,2 The survey investigated preventative treatment, finding that of the patients surveyed… 2 a A further group of patients were receiving therapies known or thought to be migraine-preventative, but for a different indication; this group of patients was referred to in the study as ‘coincidental users’ AMPP= American Migraine Prevalence and Prevention 1. Lipton et al. Neurology 2007;68(5):343–349; 2. Adapted from: Diamond et al. Headache 2007;47(3):355–363 26.3% of patients …had received preventative treatment in the past but discontinued 12.4% of patients …were currently receiving preventative treatment a 38.7% of patients …had ever used preventative therapy

33. …few patients with migraine use preventive treatment (3–13%), even though it is believed that nearly 40% of those with episodic migraine, and almost all of those with chronic migraine, in the general population would benefit American Headache Society. Headache 2019;59(1):1–18