Primary headaches are those in which headache and its associated features are the disorder in itself, whereas secondary headaches are those caused by exogenous disorders(subarchoidhemmarage, brain tumor, head injury)@@Nausea,Photophobi,Lightheadedness,Scalp tenderness,Vomiting@@Some people who get migraines have warning symptoms, called an aura, before the actual headache begins. An aura is a group of symptoms, including vision disturbances, that are a warning sign that a bad headache is coming---@@10-45yr, female, families, This sensitivity is amplified in females during the menstrual cycle. Headache can be initiated or amplified by various triggers, including glare, bright lights, sounds, or other afferent stimulation; hunger; excess stress; physical exertion; stormy weather or barometric pressure changes; hormonal fluctuations during menses; lack of or excess sleep; and alcohol or other chemical stimulation.
significant burden for both the individual and society, including loss of productivity, limitations in activity, and decreased quality of life , Migraine attacks can severely impair the ability to work and require bed rest, A recent economic model estimated that losses due to decreased productivity are roughly $1.9 million for a company with 10,000 employees
since experimental observations showedthat the diameters of the extracranial arteries in migraine patientswere dilated. Consequently, the firstclass of drugs proposed for the treatment of migraine was thosethat produce vasoconstriction.The second hypothesis, the neurological theory, considersmigraine attacks as a result of neuronal events, occurring in different brain areas and mediated by alterations in neurotransmision system.3This theory regards as amajor pathogenic step of migraine the release of inflammatoryneuropeptides from the trigeminal system, with a consequentdilatation of meningeal vessels.
Support of the vascular theory comes from studies demonstrating oligemia during migraine aura, and increase in blood flow during the headache phase. Also, when a patient with migraine is given a vasodilator such as nitrate, the headache----- fuctional imaging testing shows, hypreemia starts and oligemia is not appreciated, no clear evidence of significant increase in diameter of middle cerebral atrey during migraine attack. Recent study shows migraine can be induced without dilation of vessles.( N methyl D aspertic acid &kainic acid induced hyperalgesia)
cortical spreading depression (CSD), a short-lasting, intense wave of neuronal and glial cell depolarization. CSD spreads slowly over the cortex at a rate of approximately 2–5 mm/ min and is followed by long lasting depression of neuronal activity. migraine is caused by abnormal brain activity, which can be triggered by a number of factors. However, the exact chain of events remains unclear.Karl lashley neurologist migraine patient observed his own barin activity during aura and headache and explained scotoma is due to neuronal inactivation in the region occipotal cortex and scintillation is due to hyperctivation…….. Lean given the name CSD expained detail in animal model.
In some cases, dilated superficial temporal arteries visibly pulsate. Those symptoms led migraine theorists in the 1940s to believe vascular dilation and pulsation caused the associated headache pain. Neurokinen A, substance P, Activation of these Atrigeminal fibers cause the release of CGRP(Goadsby et al., 1988) that in turn causes vasodilation of cranial blood vessels (Williamson et al., 1997c). Recent clinical trial evidence suggests that blockade of CGRP has a potent acute antimigraine effect (Olesen et al., 2003).
The key pathway for pain in migraine is the trigeminovascular input from the meningeal vessels, which passes through the trigeminal ganglion and synapses on second-order neurons in the trigeminocervical complex (TCC). These neurons in turn project in the quintothalamic tract and, after decussating in the brainstem, synapse on neurons in the thalamus. Important modulation of the trigeminovascular nociceptive input comes from the dorsal raphe nucleus, locus coeruleus, and nucleus raphe magnus
According to “US headache consortium” While headache and migraine are often considered synonymous, they are not. Migraine is always more than headache. Learning the non-headache symptoms associated with your migraine is essential to early recognition of an attack.
Acute rx stop the progression of attack, reduce the pain and functional impression, preventive- to prevent the frequency and severity of anticipated attack
Treatmnet depends on subtype, frequency, severity ,, non specific drugs used to releive the pain and associated symptome , specific treatmet controls migraine attack but the are not usefull in non headache pain disorder.
In scientific studies the percentage of people achieving pain-free status within 2 hours of treatment has been almost double for those treating early (whenheadache is mild in intensity) vs those treating when headache is moderate or severe.
NSAIDs also have important central actions in the spinal cord and brain. Both COX-1 and COX-2 are expressed in the spinal chord under basal conditions and release PGs in response to peripheral pain stimuli
Forest plot of comparison: 2 Ibuprofen 400 mg versus placeboThe proportion of participants pain-free at 2 hours with ibuprofen 400 mg was 26% (401/1553; range 14% to 33%)• The proportion of participants pain-free at 2 hours with placebo was 12% (128/1042; range 2% to 24%)The final meta analysis results, the diamond doesn’t cross the ‘line of no effect’,
Figure 3. Forest plot of comparison: 1 Paracetamol 1000 mg versus placebo, outcome: 1.3 Headache relief at 2 hours.
is a dopamine and serotonin antagonist that is used off-label to treat migraine headaches, A meta-analysis published in 2004 analyzed 13 randomized controlled trials evaluating parenteral metoclopramide for the treatment of migraine.The A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries,
Initial choice in moderate to severe migraine if it is not releved by NSAIDs and any combination, The vasoconstrictive properties of triptans are mediated by an action on 5-HT1B in arterial smooth muscle, it is still unclear whether triptan activation of vascular 5-HT1B receptors is necessary for the treatment of migraine, capacity of these receptors to cause constriction of intracranial blood vessels including arteriovenous anastomoses, both 5-HT1B and 5-HT1D receptors serve as presynaptic autoreceptors
abnormal activation of nociceptors in the dura mater triggers vascular changes, including plasma protein extravasation (PPE), In animal models and in humans, CGRP is elevated in the external jugular vein after stimulation of the trigeminal ganglion as well as during migraine attacks. Consistent with a peripheral action for triptans, treatment with sumatriptan reduces CGRP levels as the migraine subsides
predominantly in patients with risk factors for coronary artery disease
In order to select one drug among 8 aviabletritan in market, for treatment in patient, NNT, DNT is gives very valuable information about efficay and cost effictivenees,,,,,,,,,,, number of patients who must be treated in order for one patient to derive a desired level of efficacy from the treatment…… When currently aviaable triptan were comparered using a NNT/ DNT showed– most of studies has done using primary endpoint as headache response within 2hr of post treatment. To measure the Therapeutical effectiveness NNT is better primary endpoint then traditional headche response of 2hr after treatment,,, this placebo effect is also included, BUT, Funding for this research was provided by Pfizer, Inc., manufacturer of eletriptan,
No. of doses needed to treat in a population to achive a desired level of efficacy in one patient, DNT 1 signify single dose is effective in all patinets.
The multiple pharmacological effects of ergot alkaloids have complicated the determination of their precise mechanism of action in the acute treatment of migraine
Nausea about 10% is most probably caused by a direct effect onCNSemetic centres. Ergotamine has a low degree of receptor selectivity which increases the risk of experiencing a drug-induced side-effect,,,,,,,,,,,,, contraindicated in pregnant because the drugs may cause fetal distress and miscarriage
Contraindication – pregnancy, peripheral vascular disease, coronary hearth disease, uncontrolled hypertension, stroke, impaired hepatic or renal function, and sepsis. ergotamine should not be taken within 6 h of the use of triptans, and similarly triptans should not be administered within24hof ergotamine.
Aim- reduce the frequency, duration and/or severity of migraine attack. Improving the responsiveness to acute
a , FDA approved, b inconclusive
Amitriptyline is a first-line agent for migraine prophylaxis4 and is the only antidepressant with consistent evidence supporting its effectiveness for this use Use of antidepressants in migraine prophylaxis is based on the hypothesis of dysfunction of central 5-HT availability in migraine. Depression and migraine can be considered disorders of low brain serotonergic activity.
Discovered by chance, no beta 1 since selective(metaprolol), non selective(propronolol) both are effective drugs, atenololtimolol are not lipophilic, so penetration into CNS not, ,,, B blockers with intrensicsympathomimetic action , pindolol, acebutolol fail to demonstrate effcicacy in migraine.
Efficacy – reduction in frequency of attack.
AED might increase threshold of induction of CSD, reduce the progression.
VPA, by enhancing GABAergic inhibition, reduces the neurogenic inflammation implicated in migraine , A heterozygous missense mutation in the neuronal voltage-gated Na+ channel gene SCN1A has been found in families with FHM and also in some forms of epilepsy, Sensitization of sensory neurons following the release of inflammatory mediators is associated with an increase in Na+ conductance , and increases in the expression of Na+ channels occur in models of persistent inflammation……….. VPA and TPM inhibit the persistent Na+ current at concentrations lower than those blocking the fast Na+ current. rapidly activating and inactivating “transient” Na currents that are grossly similar across cells. Nevertheless, neurons differ in the amplitude of “persistent” Na current remaining after transient currents inactivate …. VPA decreases dural plasma extravasation induced either by trigeminal stimulation or by intravenous substance P administration . The same effect is caused by muscimol, a GABAA receptor agonist
1d failed in human,,,,,,,,,, L– reached Phase 2 trial,
First, CGRP is located on sensory terminals of the trigeminal nerve, and is released following stimulation of the nerve,
The rate of response to pain two hours after treatment — the main end point of the study — was significantly higher after the infusion of BIBN 4096 BS than after the infusion of placebo………. Significantly more patients (66%) reported relief of headache (primary endpoint, improvement from moderate or severe pain to mild or none at 2hr)
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, orquisqualate receptor) is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fastsynaptic transmission in the central nervous system (CNSMerck discontinued the development of telcagepant, a promising new drug which represents a new class of migraine drugs, so-called CGRP antagonists. These drugs appear to be as effective as sumatriptan (Imitrex) and other triptans in aborting a migraine attack, but do not carry an increased risk of strokes and heart attacks which can occur, albeit very rarely, with triptans. Telcagepant was also tested as a daily preventive dr ug for migraines and in those trials some patients developed minor liver abnormalities
Pharmacotherapy of migraine
Pharmacotherapy of Migraine Dr Manukumar Post graduate Dept of Pharmacology VMMC & Safdarjung hospital
• Outline• Migraine• Pathophysiology Theories Vascular theory Neurogenic theory Neurovascular theory• Acute treatment of migraine Non-specific treatment Specific treatment• Preventive treatment of migraine• Newer targets and drugs
Migraine headache First description of migraine with visual aura.• Second most common type of primary headache• Migraine is chronic neurological disorder characterized by episodic attacks of headache and associated symptoms.• Migraine prevalence is approximately 18% in females and 6% in males.• The brain of the migraineur is particularly sensitive to environmental and sensory stimuli.
• A recent economic model estimated that losses due to decreased productivity are roughly $1.9 million for a company with 10,000 employees
Pathophysiology of migraine• Vascular theory-attributes the phenomenon of vasodilatation.• Neurogenic theory- neuronal events, cortical spreading depression.• Third theory - accommodate vascular modifications with neuronal dysfunction.
Vascular theory• Harold G Wolff first one to explain• Vasoconstriction and ischemia accounts for symptoms of migraine aura,• Reactive vasodilatation activate primary sensory neurons.• Therapies provides evidence for this theory.
Cortical spreading depression• NMDA receptors involved in the genesis and propagation of CSD. CSD was blocked by NMDA receptors antagonists in various experimental models Long lasting depression of neuronal activity.
Cortical spreading depression perivascular trigeminal and parasympathetic nerve activation, release of vasodilator mediators, CGRP, neurokinen A, substance P (pain signal)trigeminal ganglion trigeminal nucleus caudalis trigeminocervical complex
Pharmacological treatment of migraine includesAcute (abortive) treatmentPreventive (prophylaxis) treatment
Goals for acute treatment1. Treat attacks rapidly and consistently without recurrence.2. Restore the patient’s ability to function.3. Minimize the use of back-up and rescue medications.4. Be cost-effective for overall management.5. Have minimal or no adverse events.
Non-specific Rx of migraine “NSAIDs”• PGE2 and PGI2 reduce the threshold to stimulation of nociceptors, causing peripheral sensitization• CGRP release from the terminals of the trigeminal sensory neurons is modulated by PGE2• Blockade cyclooxygenase (COX) and hence reduced synthesis of PG
Forest plot of comparison: Ibuprofen 400 mg versus placebo 26% 12%• Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD008039
Anti-emetics/caffeine – combination with NSAIDs• Metoclopramide effective for nausea and vomiting associated with certain types of headaches.• D2 antagonistic action might be responsible for relieve of migraine• Caffeine, Block the adenosine receptor, Vasoconstricting action.
Efficacy and Safety of Acetaminophen, Aspirin, and Caffeine in Alleviating Migraine Headache Pain: Double-blind, Randomized, Placebo-Controlled Trials• Arch Neurol. 1998;55(2):210-217
Specific acute treatment• Triptan-Sumatriptan, naratriptan, rizatriptan, eletriptan, zolmitriptan, almotriptan & frovatriptan• Selective activity on 5-HT1B/1D agonist.• Mechanisms of action Cranial vasoconstriction Modulating neurotransmitter release from neuronal terminals.
• The triptans -preventing the peripheral release of vasoactive peptides (CGRP), reduce PPE.• Also inhibit the abnormal activation of peripheral nociceptors.• The 5-HT1D receptor-selective agonist PNU- 142633 showed greater potency than sumatriptan in blocking electrically induced PPE, and had little to no detectable vascular activity in carotid, meningeal arteries
Adverse Effects and Contraindications• coronary artery vasospasm, transient myocardial ischemia, atrial and ventricular arrhythmias, MI• Irritation at the site of injection. The most common side effect of sumatriptan nasal spray is a bitter taste.• Contraindicated- coronary artery disease , history of stroke or transient ischemic attacks, cerebrovascular or peripheral vascular disease,
Ergot alkaloids• The pharmacological effects of the ergot alkaloids are varied and complex; partial agonists or antagonists at serotonergic, dopaminergic, and adrenergic receptors• Ergot alkaloids at 5-HT1B/1D receptors likely mediate their acute anti-migraine effects
Selection of patients – ergot• Which patients? Patients requiring migraine-specific therapy Patients established on ergotamine• Special cases Patients with very long attacks Patients with frequent headache recurrence
Adverse Effects and Contraindications of Ergot Alkaloids• Nausea and vomiting, due to a direct effect on CNS emetic center.• contraindicated in pregnant, peripheral vascular disease, coronary artery disease, hypertension, impaired hepatic or renal function• In contrast to triptans, the contractile effect of ergotamine in the human isolated coronary artery is long- lasting and persists even after repeated washings
• Comparison of vasoconstriction action of ergotamine and triptan• MaassenVanDenBrink et al., 1998
Indications1. Two or more attacks per month that significantly interfere with the patient’s daily routine activity2. An unsatisfactory response to acute therapy3. contraindication to acute treatments and adverse effects (AEs) related to them.4. Uncommon migraine conditions, including hemiplegic migraine, migraine with prolonged aura or migrainous infarction.
The potential mechanisms of migraine preventive medications• Raising the threshold to migraine activation by stabilizing a more reactive nervous system• Enhancing antinociception• Inhibiting CSD• Inhibiting peripheral and/or central sensitization• Blocking neurogenic inflammation
Antidepressants• Amitriptyline alters the 5-HT synthetic rate at the dorsal raphe nucleus.• Enhancement of the pain threshold produced by AMT seems to be mediated by sodium channels, L-type calcium channels inhibition.• Chronic daily administration of AMT suppresses CSD, whereas acute treatment is ineffective.
50% reduction in migraine headaches TCA Vs placeboJackson, JE., et al. (2010). Tricyclic antidepressants and headaches: systematic review andmeta-analysis. Bmj, 341(oct20 1)
• SSRI- In a recent review, SSRIs resulted as efficacious as placebo for preventing migraine and less effective than TCA.• In a randomized controlled study fluoxetine, venlafaxine, duloxetine versus placebo, reduced frequency of migraine attacks, but not significant.
Beta blocker• Clinical findings support the efficacy of propranolol, timolol, atenolol, nadolol and metoprolol in migraine preventive treatment.• Exhibit high affinity for 5-HT receptor( 1a, 1b/d,2a)• propranolol blocked CSD in rats, without altering regional cerebral blood flow and systemic arterial blood pressure
Cont…• 53 studies including meta-analysis involving 2403 patients who are treated with either propranolol and/or placebo , propranolol yielded 44% reduction in migraine attack.• Two clinical trials valproic acid compared with propranolol, in both trials efficacy is identical.
Anti-epileptics• An unbalanced activity b/w excitatory glutamatergic transmission and GABAnergic inhibition, abnormal activation of voltage- operated ionic channels; Na , Ca channels , has been postulated in these two pathological condition.• “Valproate, topiramate”, gabapentin, lamotrigine are best for prophylaxis.
Cont..• VPA, TPM, Effect on voltage gated Na channels modify the neuronal excitability(CSD), role of Na channels are proved in FHM.• VPA reduces the neurogenic inflammation, plasma extravasation (Cutrer et al., 1997), possibly through a GABA-mediated mechanism
Calcium channel blockers• In an experimental model of neurogenic inflammation, blockade of L-type channels attenuates dural vasodilatation.• flunarizine could exert its antimigraine effect by reducing neural NO synthase (NOS) activity• In a double- blind study, flunarizine 5 mg/day was as effective as propranolol 160 mg/day in reducing the attack frequency.
Newer targets and drugs• Non-triptan 5-HT1 agonist, 5-HT1D agonists (PNU-109291 and PNU- 142633) are potent inhibitors of dural plasma protein extravasation (PPE) LY334370, which is a selective 5-HT1F agonist, inhibits single cell firing in the trigeminal nucleus caudalis (TNC)
CGRP antagonist- BIBN4096BS(olcegapant)• CGRP mediates dilation of cerebral vasculature and increases in cerebral blood flow.• CGRP-induced vasodilation can activate nociceptors on cerebral vessels.• In humans, intravenous human CGRP administration induces migraine-like headache in susceptible migraineurs
CGRP Antagonist BIBN 4096 BS(olcegapant) Vs placebo• N Engl J Med. 2004 Mar 11;350(11):1104-10
Nitric oxide synthase inhibitor• An intravenous infusion of nitroglycerin (NTG) releases NO, causes migraine in more than 60% of migraineurs , and activates trigeminal neurons in experimental animals.• In a small RCT, 546C88, a non-selective NOS inhibitor, was administered intravenoulsy to migraineurs during an acute attack (Lassen et al., 1998). The 2-hr headache response rate was 67% (10/15) on 546C88 versus 14% (2/14) on placebo