The Treatment of Migraine

What is a migraine?

A chronic neurological disorder characterised by recurrent moderate to severe headaches often in association with a number of autonomic nervous system symptoms. Unilateral headache lasting 2-72 hours

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What are the associated symptoms of migraine?

Nausea, vomiting, stomach cramps (peristalsis/drug absorption reduced). Photophobia, phonophobia. Pain aggravated by physical activity. Sensory/language/motor disturbance signals headache will soon occur (aura/no aura)

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What are the main factors of migraines which effects society?

Medical costs and lost productivity

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Outline the pathophysiology of migraine

Combination of neuronal mechanisms and blood vessels (arteries of scalp). Reduced blood flow. Involves serotonin and vasodilation of extra-cranial arteries

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Describe the physiological changes

Changes in 5th cranial nerve major pathway (serotonin levels decrease - release SP, CGRP and neurokinin A in meninges). Pain impulses. Cranial vasculature dilated/inflamed, dizziness, CGRP involves in pain/sensitivity to sound/light

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What are the names of the antibodies developed to CGRP?

Erenumab and Fremanezumab

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Outline the history of treating migraines

Migraine believed to be caused by evil spirit. Treatment involved drilling holes in skulls to release evil spirit. Many died from infection

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Describe the epidemiology of migraines

More common in women than men. Start between 15-24 years, most frequent at 35-45 years. More common in boys before puberty but becomes more common in females during adolescence. Women normally have no aura but frequent in men to have aura/no aura

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What are the risk factors for migraine?

Genetics (high risk in twins), psychological conditions (depression, stress, anxiety, bipolar). Physiological (menstruation, pregnancy). Environmental (light, food/caffeine)

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What are the specific triggers of migraine?

Physiological (stress, hunger, menstruation, pregnancy, menopause). Dietary (tyramine/cheese, monosodium glutamate). Chemical/medication (alcohol, nitrates, oral contraceptives). Lifestyle (stress, lack of sleep). Environmental (air, light, noise)

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What are the classifications of migraine?

Migraine with aura (classic/opthalamique - 1hr before migraine). Migraine without aura (common/vulgaire). Migraine without headache (silent - less common, aura but headache does not develop)

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What are the four phases of migraine?

Prodrome, aura, pain phase and postdrome (severity of duration and pain is variable)

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What is the term for a migraine lasting longer than 72 hours?

Status migrainosus (should be referred)

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Describe features of the prodome phase

Premonitory phase, occurs 2 hours/ 2 days before headache/pain/aura. Symptoms - altered mood, irritability, depression, euphoria, fatigue, GI disturbance, craving for certain foods, stiff muscles (neck), sensitivity to smells/noise

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Describe features of aura phase

Immediately precedes the headache. Transient neurological phenomenon. Symptoms - visual/sensory/motor, appear in minutes and last <1hr. Gain or loss of perception (negative/positive scotoma)

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What is negative scotoma (hemianopsia)?

Loss of awareness e.g. part of field of vision or hearing missing - visual aura - should not be confused with serious eye conditions

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What is positive scotoma (Scintillating Scotoma)?

Gain of awareness e.g. zig-zags in visual field, new sound - visual aura - should not be confused with PVD

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Describe features of sensory aura

Pins-and-needles in one side in hand and arm, spread to nose-mouth on same side (N.B. rule out stroke/heart attack). Migraine with motor symptoms (hemiplegic) lasts >1hr

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Describe features of the pain phase

Unilateral, throbbing, intensity varies, aggravated by physical activity, pain lasts 4-72 hours in adults (<1hr for children). Frequency varies. Light aggravates symptoms. Blurred vision, nasal stuffiness, diarrhoea, frequent urination, stiff neck

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What is a basilar migraine?

A migraine with neurological symptoms related to the brain stem or with neurological symptoms on both side of the body. Side effects - sense of world spinning, light head-aches and confusion

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Describe features of postdrome phase

Effects of migraine may persist for some days after main headache has ended. Sore feeling, impaired thinking. Tired, feel hungover, head pain, cognitive difficulties, GI symptoms, mood changes, weakness, depression, malaise (rare to feel euphoric)

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Describe features of the diagnosis of migraines

5+ attacks (migraine with aura, 2 attacks sufficient for diagnosis). 4hrs-3 days in duration. 2+ unilateral, pulsating (intensity), aggravation, avoidance of physical activity. 1+ nausea, vomiting, sensitivity to light and sound

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Describe differentiation from other types of headache

Sinus (pain behind forehead/cheekbones). Cluster (pain in/around one eye). Tension (pain like band squeezing head). Migraine (pain, nausea and visual changes, classic form)

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Outline general treatments of migraine

Analgesic as first line of treatment (NSAID - soluble/dispersible due to GI motility). 5HT1 receptor agonist (triptan). Ergot alkaloids (rarely used).

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What is medication overuse headache?

Analgesic induced headache. Excessive use of acute treatments of migraine (opioid, non-opioid analgesics, 5HT1 receptor agonists, ergotamine) - need careful management

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What are the seven treatments of migraine?

Analgesics, 5HT1 receptor agonists, ergot alkaloids, new treatments of migraine, anti-emetics, combination products, prophylaxis of migraine

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Describe features of analgesics

Most common. Dispersible/effervescent preparations used due to reduced peristalsis (reduced absorption). E.g. NSAID tolfenamic acid (POM), diclofenac potassium, flurbiprofen and ibuprofen, celecoxib

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Describe features of 5HT1 receptor agonists (Triptans)

Act on 5HT (serotonin) 1B/1D receptors (5HT 1B/1D receptor agonists). Used during established headache phase of attack, used when others fail. Use alternative 5HT1 receptor agonist if one fails. Combination with NSAID (naproxen)

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Give examples of 5HT1 receptor agonists

Almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan. Odansertron (Zofran) – treat nausea and vomiting

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Describe features of the chemistry of 5HT

Central neurotransmitter (involved in numerous behavioural systems). Peripheral signalling (mucosa, blood platelets, intestine). Phenolic hydroxyl group (pKa ~ 11). Primary aliphatic amine (pKa ~ 10). Indole moiety

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Outline the biosynthesis of serotonin

Tryptophan - tryptophan hydroxylase - 5-Hydroxytrytophan - aromatic amino acid decarboxylase - 5-Hydroxytryptamine (serotonin)

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Outline the metabolism of serotonin

Serotonin - monoamine oxidase (PNS/CNS) - 5-Hydroxyindoleacetic acid (HIA)

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Describe features of serotonin storage and release

5HT stored in vesicles close to enterochromaffin granules. 5HT tightly bound to Serotonin Binding Protein (SBP). Binding to SBP reduces osmotic pressure of 5HT. Exocytosis (5HT/SBP complex dissociates)

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Describe the structure of 5-HT1B Serotonin receptor

All 5HT receptors (except 5HT3) are GPCR that activate a secondary messenger (e.g. cAMP). 7 general classes and 14 5HT receptor types. Both excitatory/inhibitory neurotransmission. Occur in PNS and CNS

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Structure of Triptans include which particular chemical?

Serotonin. E.g. Almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan

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Describe features of Sumatriptan (Imigran)

5-HT1D agonist. Methylsulphonamide group/water solubility (21mg/mL, log P: 0.8, protein binding: 14-21%, t1/2: 2.5h). Used for treatment of migraine/cluster headaches. Doesn't cross BBB

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How does Sumatriptan affect cranial and basilar arteries?

Causes constriction of cranial and basilar arteries leading to reduced blood flow to CNS. Decreased activity of trigeminal nerve

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Describe the shape and charge similarities of Sumatriptan and Serotonin

Both have indole moiety. OH (pKa ~ 11) and NH2 (pKa ~ 10) on serotonin modified to form methylsulphonamide (pKa ~ 8) and tertiary aliphatic amine (pKa ~ 9). Resonance, zwitterionic

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Describe features of Sumatriptan dosing

Oral (50-100mg every 2h PRN). Subcutaneous (2 mg 50% relief, 8 mg 80% relief). Onset relief (subcutaneous 30 mins 95% F, oral 2h 10-15% F, nasal 20mg - faster than tablets). 3-5 times weaker agonistic effect than 5HT. No rise in BP/heart rate

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What are the side effects of Sumatriptan?

Dizziness, light-headaches, nausea, vomiting, vasoconstriction of peripheral blood vessels (coronary artery) - pharmacological effect

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What are the cautions with Triptans?

Used with caution in elderly (those with coronary heart disease). Ischaemic heart disease, MI, coronary vasospasm. Hypertension. Pregnancy (don't want to change blood vessels during growth of foetus). ADRs

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Is Naratriptan an example of a 'Me-Too' drug?

Focuses on taking a structure of a drug which is not in a patent and using that structure in a different drug modification e.g. Sumatriptan to Naratriptan

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What are the issues with Ergotamine?

Acts as an agonist at alpha-adrenoreceptors at 5HT1B/1D and D2 receptors. Low degree of receptor selectivity (high risk of drug induced side effects, issues with overdose). Avoid in patients with coronary heart disease

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Outline the structure of Ergotamine

3 H bond donor groups, 6 H acceptor groups, several hydrophobic moieties

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What are the other issues with Ergotamine?

Difficulties in absorption. Side effects include vomiting, nausea, abdominal pain and muscular cramps (best avoided). Treatment should not be repeated at intervals of <4 days. Limit administration to <twice a month

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Should Ergotamine be prescribed prophylatically?

Never prescribed prophylatically but in management of cluster headache a low dose (e.g. 1 mg at night for 6 nights in 7) occasionally given to 1-2 weeks (unlicensed medication)

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What are the new treatments for migraine?

Ketamine, Erenumab and Fremanezumab antibodies, skin cooling products, use of low intensities of green light (sunglasses)

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Describe features of anti-emetics

Given as an intramuscular injection or rectally if vomiting is a problem. Metoclopramide/domperidone promote gastric emptying and normal peristalsis (single dose given at onset of symptoms). Oral preparations convenient (warnings of extrapyramidal)

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Give examples of anti-emetics

Phenothiazine and antihistamines

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Give examples of combination products

Paramax (paracetamol, metoclopramide hydrochloride, oral powder sachets). Migril (ergotamine tartrate, cyclizine hydrochloride, caffeine hydrate). Migraleve Pink (paracetamol codeine phosphate, buclizine hydrochloride)

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Give other examples of combination products

Migramax (aspirin, metoclopramide hydrochloride, oral powder sachets). Paracetamol/Isometheptene (Midrid)

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Which combination products are less suitable for prescribing?

Migril, Migraleve Pink and Midrid

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What is the difference between Migraleve Pink Tablets and Migraleve Yellow Tablets?

Both contain 500 mg paracetamol and 8 mg of codeine phosphate but Pink contains 6.25 mg of buclizine hydrochloride (Pink taken at first sign of migraine and Yellow taken if Pink doesn't work)

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Describe features of prophylaxis of migraine

Investigate provoking factors (stress, irregular lifestyle) and chemical triggers (alcohol, nitrates). Combined oral contraceptives provoke migraine

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Which factors are considered for preventative measures?

Preventative treatments considered for patients who suffer: 2+ a month, increased frequency, disability, cannot take suitable treatment for migraine attacks. Also used for rare migraine sub-types and those at risk of migrainous infarction

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What are the prophylatic drug treatments (all POM)?

Beta blockers (propanolol), TCAs (amitrotyline), anti-epileptics (topiramate), Pizotifen, Clonidine, Botulinum Toxin Type A

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Which 5HT receptors are in the periphery?

5-HT2, 2B, 3, 4 and 7

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Describe features of 5HT2 receptors

Increase Ca release in pulmonary artery. Contractile response in vascular, urinary, GI and intestinal smooth muscle. Increased platelet aggregation

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Describe features of 5HT2B receptors

Contraction of stomach fundus. Endothelium-dependent relaxation of jugular vein and pulmonary artery. Present throughout colon and SI. Developmentally linked - mRNA increased in foetal and large intestine, levels decrease with increasing age

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Describe features of 5HT3 receptors

Regulation in cardiac function. Induction of vasodilation. Regulation of lung and intestinal function. Nausea and vomiting

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Describe features of 5HT4 receptors

Contraction of mysenteric plexus, oesophagus, colon, used in IBS, involved in GIT secretory processes, induction of tachycardia, control of bladder contraction

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Describe features of 5HT7 receptors

Relaxation of coronary artery. Prolonged stimulation leads to hypotension. Relaxation of colon and ileum

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5HT receptors in the CNS are implicated with which functions?

Food intake, thermoregulation, sexual behaviours, aggression (mood), cognitive processes, role in Schizophrenia

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What are the selective ligands which are essential when wishing to elicit peripheral effects?

Anti-emesis, muscle tone and vaso/bronchodilation

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The Treatment of Migraine

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