Headache and Migraine Applied Therapeutics PDF

University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 1 Tension-type headache Tension-type headache, the most common type of primary headache, is more common in women than men. Pain is usually mild to moderate and non-pulsatile...

University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 1 Tension-type headache Tension-type headache, the most common type of primary headache, is more common in women than men. Pain is usually mild to moderate and non-pulsatile. Episodic headaches may become chronic in some patients. Premonitory symptoms and aura are absent, and pain is usually mild to moderate, bilateral, non-pulsatile, and in the frontal and temporal areas, but occipital and parietal areas can also be affected. Mild photophobia or phonophobia may occur. Pericranial or cervical muscles may have tender spots or localized nodules in some patients. Treatment Non-pharmacologic therapies include reassurance and counseling, stress management, relaxation training and biofeedback. Physical therapeutic options (e.g., heat or cold packs, ultrasound, electrical nerve stimulation, massage, acupuncture, trigger point injections, and occipital nerve blocks) have performed inconsistently. Simple analgesics such as paracetamol (alone or in combination with caffeine or butalbital) and NSAIDs (such as aspirin, diclofenac, ibuprofen, naproxen, ketoprofen and ketorolac) are the mainstay of acute therapy. A preventive treatment is to be considered if headache frequency is more than two per week, duration is longer than 3 to 4 hours or severity results in medication overuse or substantial disability. The TCAs are used most often for prophylaxis of tension headache, but venlafaxine, mirtazapine, gabapentin, topiramate and tizanidine may also be effective. Migraine Migraine, a common, recurrent, primary headache of moderate to severe intensity, interferes with normal functioning and is associated with gastrointestinal, neurologic and autonomic symptoms. In migraine with aura, focal neurologic symptoms precede or accompany the attack. Activation of trigeminal sensory nerves triggers the release of vasoactive neuropeptides, including calcitonin gene-related peptide, neurokinin A and University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 2 substance P from perivascular axons. Vasodilation of dural blood vessels may occur with extravasation of dural plasma resulting in inflammation. Studies suggest 50% heritability of migraine, with a multifactorial polygenic basis. Migraine triggers may be modulators of the genetic set point that predisposes to migraine headache. Specific populations of serotonin (5-HT) receptors appear to be involved in the pathophysiology and treatment of migraine headache. Ergot alkaloids and triptan derivatives are agonists of vascular and neuronal 5-HT1 receptors, resulting in vasoconstriction and inhibition of vasoactive neuropeptide release. Triggers of Migraine: Behavioral–physiologic Food triggers Environmental triggers triggers ▪ Alcohol ▪ Glare or flickering lights ▪ Excess or insufficient sleep ▪ Caffeine/caffeine withdrawal ▪ High altitude ▪ Fatigue ▪ Chocolate ▪ Loud noises ▪ Menstruation, menopause ▪ Fermented and pickled foods ▪ Strong smells and fumes ▪ Sexual activity ▪ Monosodium glutamate (e.g., ▪ Tobacco smoke ▪ Skipped meals in Chinese food, seasoned ▪ Weather changes ▪ Strenuous physical activity salt, and instant foods) (e.g., prolonged ▪ Nitrate-containing foods overexertion) (e.g., processed meats) ▪ Stress or post stress ▪ Saccharin/aspartame (e.g., diet foods or diet sodas) ▪ Tyramine-containing foods Clinical presentation and diagnosis Migraine headache is characterized by recurring episodes of throbbing head pain, frequently unilateral. Approximately 12% to 79% of patients with migraine (=migraineurs) have premonitory symptoms (prodrome) in the hours or days before headache onset. Migraine headache may occur at any time but usually occurs in the early morning. Pain is usually gradual in onset, peaking in intensity over minutes to hours and lasting 4 to 72 hours. Pain is typically in the frontotemporal region and is moderate to severe. Headache is usually unilateral throbbing. University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 3 Other symptoms include: Neurologic phonophobia, photophobia, hyperosmia, and difficulty symptoms concentrating Psychological anxiety, depression, euphoria, irritability, drowsiness, symptoms hyperactivity and restlessness Autonomic e.g., polyuria, diarrhea and constipation symptoms Constitutional e.g., stiff neck, yawning, thirst, food cravings and anorexia symptoms Aura A migraine aura is experienced by approximately 25% of migraineurs. Aura evolves over 5 to 20 minutes and lasts less than 60 minutes. Headache usually occurs within 60 minutes of the end of the aura. Visual auras can include both positive features (e.g., scintillations, photopsia, teichopsia, and fortification spectrum) and negative features (e.g., scotoma and hemianopsia). Sensory and such as paresthesias or numbness of the arms and face, motor dysphasia or aphasia, weakness, and hemiparesis may also symptoms occur. GI symptoms e.g., nausea and vomiting in addition to anorexia, constipation, diarrhea and abdominal cramps Sensory photophobia, phonophobia, or osmophobia hyperacuity They are frequent. Many patients seek a dark, quiet place. Other systemic symptoms include nasal stuffiness, blurred vision, diaphoresis, facial pallor, and localized facial, scalp or periorbital edema. Once the headache pain wanes, a resolution phase (postdrome) characterized by exhaustion, malaise, and irritability ensues. A comprehensive headache history is essential and includes age at onset; frequency, timing, and duration of attacks; possible triggers; ameliorating factors; description and characteristics of symptoms; associated signs and symptoms; treatment history; and family and social history. Neuroimaging should be considered in patients with unexplained abnormal neurologic examination or atypical headache history. Onset of migraine headaches after age 50 suggests an organic etiology, such as a mass lesion, cerebrovascular disease or temporal arteritis. University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 4 Treatment Pharmacologic agents used for the treatment of migraine can be classified as abortive (i.e., for alleviating the acute phase) or prophylactic (i.e., preventive). The goal is to achieve consistent, rapid headache relief with minimal adverse effects and symptom recurrence, and minimal disability and emotional distress. It is recommended to limit use of acute migraine therapies to avoid development of medication-misuse headache. Non-pharmacologic Treatment Non-pharmacologic treatment includes: Ice application to the head and periods of rest or sleep. Identification triggers of migraine to avoid them. Behavioral interventions (relaxation, biofeedback and cognitive therapy) Occipital nerve stimulators may be helpful in patients whose headaches are refractory to other forms of treatment. Non-pharmacologic Therapies Tested in Clinical Trials Behavioral Treatments Physical Treatments Relaxation training Acupuncture Hypnotherapy Transcutaneous electrical nerve Thermal biofeedback training stimulation (TENS) Electromyographic biofeedback therapy Occlusal adjustment Cognitive/behavioral management Cervical manipulation therapy Pharmacologic Treatment of Acute Migraine An acute migraine therapy should be used at the onset of migraine. Soluble preparations are best because gut motility is reduced during a migraine attack, and absorption of oral medication may be delayed. Pretreatment with an antiemetic (e.g., metoclopramide, chlorpromazine, or prochlorperazine) 15 to 30 minutes before oral or non-oral migraine treatments (rectal suppositories, nasal spray, or injections) may be advisable when nausea and vomiting are severe. In addition to its antiemetic effects, metoclopramide helps reverse gastroparesis and enhances absorption of oral medications. University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 5 Frequent or excessive use of acute migraine medications can result in increasing headache frequency and drug consumption known as medication- overuse headache. ✓ Analgesics and NSAIDs Simple analgesics and NSAIDs are first-line treatments for mild to moderate migraine attacks; some severe attacks are also responsive. Aspirin, diclofenac, ibuprofen, ketorolac, naproxen sodium, tolfenamic acid, and the combination of acetaminophen plus aspirin and caffeine or butalbital are effective. In case of nausea and vomiting, rectal and IM routes are considered to administer NSAIDs. ✓ Ergot alkaloids and derivatives Ergot alkaloids are useful for moderate to severe migraine attacks. They are nonselective 5HT1 receptor agonists that constrict intracranial blood vessels and inhibit the development of neurogenic inflammation in the trigeminovascular system. Venous and arterial constriction occurs. They also have activity at dopaminergic receptors. Ergotamine tartrate is available for oral, sublingual, and rectal administration. Oral and rectal preparations contain caffeine to enhance absorption and potentiate analgesia. Dihydroergotamine is available for intranasal and parenteral (IM, IV or SC) administration. Nausea and vomiting are common with ergotamine derivatives, so they are better to be used with antiemetic pretreatment. Use of ergotamine derivatives and triptans within 24 hours should be avoided. Contraindications to use of ergot derivatives include renal and hepatic failure; coronary, cerebral, or peripheral vascular disease; uncontrolled hypertension; sepsis; and women who are pregnant or nursing. ✓ Serotonin receptor agonists (triptans) The triptans (5HT1B/1D-agonists) are appropriate first-line therapies for patients with mild to severe migraine or as rescue therapy when nonspecific medications are ineffective. Sumatriptan is available in oral and intranasal formulations and SC injection. University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 6 Second-generation triptans (frovatriptan, naratriptan, zolmitriptan, almotriptan, eletriptan and rizatriptan) have higher oral bioavailability and longer half-lives than oral sumatriptan, which could theoretically reduce headache recurrence. Lack of response to one triptan does not preclude effective therapy with another triptan. Contraindications include ischemic heart disease, uncontrolled hypertension, cerebrovascular disease, hemiplegic and basilar migraine, and pregnancy. A cardiovascular assessment should be done before giving triptans to postmenopausal women, men over 40 years of age, and patients with uncontrolled risk factors. First dose should be administered under medical supervision. Ergot alkaloids and triptans should not be used concomitantly. A 24 hours’ period is the minimum period to switch to the other agent. ✓ Serotonin 5-HT1F Agonists (Ditans) Serotonin 5-HT1F receptor agonists (ditans) do not elicit a vasoconstrictive effect, whereas triptans cause vasoconstriction via agonistic action at 5-HT1B/1D receptors. Because of this ditans may be used for acute migraine attacks in patients with cardiovascular risks. Lasmiditan (first drug in this class) was approved in the United States in October 2019. ✓ Opioids Opioids and derivatives (e.g., meperidine, butorphanol, oxycodone, and hydromorphone) are reserved for patients with moderate to severe infrequent headaches in whom conventional therapies are contraindicated or as rescue medication after failure to respond to conventional therapies. ✓ Barbiturates Some barbiturates (like butalbital) are used in combination with aspirin and paracetamol for pain relief and to induce sleep. Caffeine is also used to increase GI absorption. They are associated with rebound headaches. University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 7 ✓ Antiemetics Antiemetic agents are effective if nausea and vomiting are prominent features. They also may act as prokinetics to increase gastric motility and enhance absorption. Antiemetic agents are used to treat migraine and the emesis associated with acute attacks. ✓ Antipsychotics Chlorpromazine can be used as monotherapy for acute migraine headaches. ✓ Anti-CGRP agents Calcitonin gene-related peptide (CGRP) is a potent vasodilator and is a key neuropeptide that is central to migraine pathophysiology. Anti-CGRP agents were developed. Some non-peptide small molecules are indicated for the treatment of migraines in adults including Rimegepant, ubrogepant, and zavegepant. Pharmacologic Prophylaxis of Migraine Prophylactic therapies are administered daily to reduce the frequency, severity and duration of attacks, and to increase responsiveness to acute therapies. Only propranolol, timolol, divalproex sodium, and topiramate are FDA-approved for migraine prevention. Prophylactic therapy continues for at least 6 to 12 months after headache frequency and severity have diminished, and then gradual tapering or discontinuation may be reasonable. Prophylactic therapy is indicated in cases: 1. Recurring migraines that produce significant disability (i.e. headaches cause major disruptions in the patient’s lifestyle, with significant disability that lasts 3 or more days). 2. Frequency of migraine attacks is greater than twice per month. 3. Frequent attacks requiring symptomatic medication more than 2 per week. 4. Duration of individual attacks is longer than 24 hours. 5. Symptomatic therapies that are ineffective, contraindicated, or produce serious side effects. 6. Uncommon migraine variants that cause profound disruption or risk of neurologic injury. University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 8 7. Patient preference to limit the number of attacks. 8. Preventive therapy may also be given intermittently when headaches recur in a predictable pattern (e.g., exercise-induced or menstrual migraine). ✓ Analgesics and NSAIDs NSAIDs are modestly effective for reducing the frequency, severity and duration of migraine attacks. Evidence for efficacy is strongest for naproxen and weakest for aspirin. They may be used intermittently to prevent headaches that recur in a predictable pattern (e.g., menstrual migraine). Treatment should be initiated 1 or 2 days before the time of headache vulnerability and continued until vulnerability is passed. Patients who not respond to routine abortive treatment may require additional analgesics. Practice guidelines recommend nonopioid medications as first-line therapy. Opioid analgesics should be used sparingly, but they remain an option. ✓ Β-adrenergic antagonists Propranolol, timolol and metoprolol reduce the frequency of migraine attacks. Atenolol and nadolol are probably also effective. β-Blockers with intrinsic sympathomimetic activity (oxprenolol, pindolol, penbutolol, labetalol and acebutolol) are ineffective. β-Blockers should not be used as first-line agents for migraine prophylaxis in smokers over age 60 years. ✓ Anticonvulsants Valproic acid, divalproex sodium and topiramate can reduce the frequency, severity and duration of headaches. 50% of patients respond to topiramate. Paresthesias and weight loss are common side effects. ✓ Antidepressants The tricyclic antidepressants (TCA) amitriptyline and venlafaxine are probably effective for migraine prophylaxis. There are insufficient data to support or refute the efficacy of other antidepressants. Their beneficial effects in migraine prophylaxis are independent of antidepressant activity. University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 9 TCAs are usually well tolerated at the doses used for migraine prophylaxis, but anticholinergic effects may limit use, especially in elderly patients or those with benign prostatic hyperplasia or glaucoma. Evening doses are preferred because of sedation. SSRIs (including sertraline, fluoxetine and paroxetine) have limited efficacy for migraine prophylaxis in adults. They are not recommended in children. ✓ Serotonin receptor agonists (triptans) Serotonin 5-HT receptor agonists or triptans (frovatriptan, naratriptan and zolmitriptan) may be used in prophylaxis of menstrual migraine. ✓ Calcium channel blockers Calcium channel blockers are commonly used as prophylactic medication for migraine. Flunarizine has the best-documented efficacy. Verapamil has been widely used and supported by studies, but evidence for efficacy is inadequate. ✓ Anti-CGRP agents Calcitonin gene-related peptide (CGRP) is a potent vasodilator and is a key neuropeptide that is central to migraine pathophysiology. Anti-CGRP agents were developed. They are indicated for preventive treatment of migraines in adults. Prophylactic anti-CGRP agents include: non-peptide small molecules Rimegepant Orally Atogepant Monoclonal CGRP-receptor Erenumab Subcutaneously antibodies antagonists Once monthly antagonists of Fremanezumab CGRP molecule Galcanezumab Eptinezumab intravenously every 3 months ✓ Botulinum toxin A Injections of OnabotulinumtoxinA (Botox) may be beneficial in patients with intractable migraine headaches that fail to respond to at least 3 conventional preventive medications. This agent is not recommended for use in the preventive treatment of episodic migraines. University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 10 ✓ First generation antihistamines Promethazine is a phenothiazine derivative that possesses antihistaminic, sedative, anti m ̶ otion-sickness, antiemetic, and anticholinergic effects. It has potent serotonin antagonist activity have been reported to be effective in the treatment of migraine. Cyproheptadine and pizotifen are first-generation antihistamine with anticholinergic and antiserotonergic properties. They are no more recommended as first line agents in the prophylaxis of migraine. ✓ 5-HT2 antagonism Methysergide is no more recommended. Complementary and Alternative Treatments Herbal products, such as: Butterbur (Petasites) is established as effective and the guideline highly recommend it for migraine prevention. Feverfew (Tanacetum parthenium L.) is a medicinal plant traditionally used for the treatment of migraine headaches. Other agents include: Riboflavin (vitamin B2) and Magnesium: A study of high-dose riboflavin (400 mg) found that riboflavin was superior to placebo in reducing attack frequency and headache days. Coenzyme Q10: It is effective and well tolerated for migraine prophylaxis, but there is no long- term difference in headache outcomes between the CoQ10 and placebo groups. Melatonin is not significantly superior statistically to the reduction seen with placebo. Status Migrainosus Treatment Approximately 40% of all migraine attacks do not respond to a given triptan or any other substance. Those patients may be considered to suffer from intractable migraine or status migrainosus with associated vomiting. If conventional treatment failed or an attack lasting longer than 72 hours, some patients may need to be hospitalized for a short period. They may require parenteral therapy with ergot derivatives (i.e. dihydroergotamine), valproate, sumatriptan, or potent narcotic analgesics (morphine or meperidine) for a few days. University of Anbar - College of Pharmacy Applied Therapeutics I – Headache and Migraine 11 Corticosteroids (e.g., prednisone 40-60 mg orally for 3-5 days or dexamethasone 4-24 mg intravenously or intramuscularly) may be considered as alternative treatments for intractable migraine. Prochlorperazine is used antiemetic and chlorpromazine is effective to pain relief from intractable migraine with antiemetic properties. Treatment of Menstrual Migraine Abortive therapy for menstrual migraine is the same as for non-menstrual migraine. Patients with frequent and severe attacks may benefit from short-term, perimenstrual use of preventive agents (e.g., frovatriptan). Patients who do not respond to standard preventive measures may benefit from hormonal therapy. Perimenstrual estrogen supplementation with estradiol (orally or transdermally) may be beneficial.