Dr Niazy B Hussam Aldin PhD Clinical Pharmacy HEADACHE Dr Niazy B Hussam Aldin PhD Clinical Pharmacy

Headache • Headache is a symptom that can be caused by many disorders for example, traction, inflammation of pain-sensitive structures within the head, or it can be due to disorders of extracranial structures such as the eyes, ears, or sinuses. • Headache can be categorized on the basis of the underlying etiology into one of two major types (primary and secondary).

Prevalence and Impact PREVALENCE 112 million bedridden days per year 18-25 % women have migraine 6-10 % men have migraine 5% of women have headache more than 15 days per month 112 million bedridden days per year Cost to U.S. Employers -- $13 Billion per year The majority of patients with migraine have not received an appropriate diagnosis, and are not receiving appropriate therapy

Classification Primary headache disorders are characterized by the lack of an identifiable and treatable underlying cause. Migraine, tension-type, and cluster headaches are examples of primary headache disorders. • Secondary headache disorders are those associated with a variety of organic causes such as trauma, cerebrovascular malformations, and brain tumors.

Classification of primary Headache • Migraine • Migraine without aura • Migraine with aura • Complicated migraine • Tension-Type Headache • Episodic tension-type headache • Chronic tension-type headache • Cluster Headache • Episodic cluster headache • Chronic cluster headache

Classification of secondary Headache • Headache Associated with Head Trauma • Acute post-traumatic headache • Chronic post-traumatic headache • Headache Associated with Vascular Disorders • Acute ischemic cerebrovascular disease ( stroke) • Intracranial hematoma • Subarachnoid hemorrhage • Headache Associated with Metabolic Disorder • (e.g., hypoxia, hypercapnia, hypoglycemia, dialysis) • Miscellaneous Headaches Unassociated with Structural Lesion • (e.g., cold stimulus headache)

Primary Headache Disorders • Migraine Headaches • It is usually develop over a period of minutes to hours, progressing from a dull ache to a more intense pulsating pain that worsens with each pulse. • The headache usually begins in the front temporal region and may radiate to the occiput and neck; it may occur unilaterally or bilaterally.

Cluster Headaches • Cluster headaches derive their name from a characteristic pattern of recurrent headaches that are separated by periods of remission that last from months to even years. During those periods the headaches usually occur at least once daily. The headache generally is unilateral, occurs behind the eye, reaches maximal intensity over several minutes, and lasts for <3hrs • Unilateral lacrimation, rhinorrhea, and facial flushing may accompany the cluster headache. During cluster periods, headache is commonly precipitated by alcohol, naps, and vasodilating drugs. In contrast to migraine headaches, cluster headaches are more common in males than females.

Tension-Type Headaches • It is the most common type of primary headache and is more common in women than men. Pain is usually mild to moderate and non pulsating. It is also described as dull, persistent headache, occurring bilaterally in a hatband distribution around the head. The headache may fluctuate in intensity throughout the day. • Tension-type headaches often occur during or after stress, but chronic tension-type headaches may persist for months even in the absence of recognizable stress. • Skeletal muscle over contraction, depression, and occasionally nausea may accompany the headache. • Neurologic symptoms do not occur in association with tension-type headache. • Mild photophobia or phonophobia occur in some patient.

Secondary Headache Disorders • Are those associated with a variety of organic causes. • A new severe headache in a patient without a previous history is the most useful sign for identifying potentially destructive intracranial or extracranial causes of headache. • Such headaches may develop suddenly, over a period of hours to days (acute headache), or more gradually over days to months (subacute headache) .

Acute Headaches Acute headaches can be symptomatic of subarachnoid hemorrhage, stroke, meningitis, or intracranial mass lesion (e.g., brain tumor, hematoma, abscess). • The headache that accompanies subarachnoid hemorrhage is typically severe (often described by the patient as the “worst headache of my life”) and may occur in conjunction with alteration of mental status and focal neurologic signs. • The headache of meningitis is usually bilateral and develops gradually over hours to days; symptoms such as fever, photophobia, and positive meningeal Kernig's signs, (which is a resistance to extension of the leg when the hip is flexed, due to meningeal irritation in the lumber area) often accompany the meningeal headache. Subacute Headaches • Subacute headaches may be a sign of increased intracranial pressure, intracranial mass lesion, sinusitis, or trigeminal neuralgia

Pathophysiology • Intracranially, only a limited number of structures are sensitive to pain. • Headache may result from dilation, distention, or traction of the large intracranial vessels. • The brain itself is insensitive to pain. Whereas scalp arteries and muscles are capable of registering pain and have been implicated in the pathophysiology of migraine and tension-type headache. • Extracranially, most of the structures outside the skull (e.g., eye, ear, teeth, skin, deeper tissues) have pain afferents.

Historically, the primary headache disorders have been thought to be related either to vascular disturbances (migraine and cluster headache) or muscular tension (tension-type headache). • However, a neurovascular hypothesis proposed that headache is triggered by disturbances in central pain processing pathways leading to the release of serotonin, a vasoactive neurotransmitter which plays a role in migraine pathogenesis. • That is why, drugs that alter serotonergic function are highly effective for the symptomatic treatment of migraine and cluster headache.

Migraine headache Symptoms • It is characterized by recurring episodes of throbbing head pain, frequently unilateral. It can be severe and associated with nausea, vomiting, and sensitivity to light, sound, and/or movement. • The migraine headache may occur at any time of day or night but usually occurs in the early morning hours on awakening. • Pain is usually gradual in onset, peaking in intensity over minutes to hours, and lasting between 4 and 72 hours untreated. Pain is typically reported as moderate to severe and most often involves the frontotemporal region.

• Approximately 20% - 60% of migraineurs experience premonitory symptoms (not to be confused with aura) in the hours or days before the onset of headache including: • Neurologic symptoms (phonophobia, photophobia, & difficulty in concentrating) • psychological symptoms (anxiety, depression, euphoria, irritability, drowsiness, hyperactivity & restlessness), • autonomic symptoms (polyuria, diarrhea & constipation • constitutional symptoms (stiff neck, thirst, anorexia & food cravings ) .

• A migraine aura • Experienced by approximately 31% of sufferer • A migraine aura • Experienced by approximately 31% of sufferer. The aura typically 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, means experience flashing lights, , photopsia means light stimuli that observed when the eyes are closed , teichopsia, the appearance of zigzag lines before the eyes)

•. negative features (e. g • * negative features (e.g., scotoma, notice a black spot at the corner of the eye which impedes peripheral vision, hemianopsia, decreased vision or blindness takes place in half the visual field of one or botheyes. ). • There are sensory and motor symptoms such as paresthesia or numbness of the arms and face, dysphasia or aphasia and weakness may also occur. • Many patients seek a dark, quiet place for rest and relief. • Once the headache pain wanes, a resolution phase characterized by exhaustion, malaise, and irritability ensues.

• DIAGNOSIS • • In the headache evaluation, diagnostic alarms should be identified, including: • “first” or “worst” headache ever, • onset of the headache • Is it associated with systemic illness ( fever, nausea, vomiting & stiff neck) • focal neurologic symptoms or papilledema, • absence of daily headache, • positive family history for migraine, • presence of food triggers, • menstrual association, • long-standing history, • improvement with sleep,

Check for abnormalities: • vital signs (fever, hypertension), • funduscopy (papilledema, hemorrhage, and exudates), • trigger points • neurologic examination (abnormalities or deficits in mental status) • Neuroimaging computed tomography (CT) or magnetic resonance imaging (MRI) should be considered in patients with unexplained findings on the neurologic exam & those with additional risk factors • LABORATORY TESTS • • In secondary headache presentation, serum chemistries, and other blood tests, such as a complete blood count, antinuclear antibody titer, ESR and antiphospholipid antibody titer as well as thyroid function tests may be considered. ,

Commonly Reported Triggers of Migraine • Food triggers • Alcohol • caffeine withdrawal • Chocolate • Fermented foods • Monosodium glutamate (e.g., in Chinese food, and instant foods) • Nitrate-containing foods (e.g., processed meats) • Saccharin/aspartame (e.g., diet foods or diet sodas) • Tyramine-containing foods

• Environmental triggers • Glare lights • High altitude • Loud noises • Strong smells and fumes • Tobacco smoke • Weather changes • Behavioral–physiologic triggers • Excess or insufficient sleep • Fatigue • Menstruation, menopause • Skipped meals • Strenuous physical activity ( prolonged overexertion) • Stress or post-stress

• TREATMENT • Nonpharmacologic Treatment • Preventive management should begin with identification and avoidance of factors that provoke migraine attacks. • Application of ice to the head and periods of rest or sleep, usually in a dark, quiet environment, may be beneficial. • Behavioral interventions (relaxation therapy , cognitive therapy) are preventive options for patients who prefer nondrug therapy or when drug therapy is ineffective or not tolerated.

Pharmacologic Treatment of Acute Migraine • Acute migraine therapies are most effective when administered at the onset of migraine. • The frequent or excessive use of acute migraine medications can result in a pattern of increasing headache frequency and drug consumption phenomena known as medication-over ruse headache. • This occurs commonly with overuse of simple or combination analgesics, ergotamine tartrate, opiates and triptans. This may be avoided by limiting use of acute migraine therapies to 2 or 3 days per week.

• 1-Pretreatment with antiemetics (prochlorperazine, metoclopramide) • Given 15 to 30 minutes prior to administering oral acute migraine therapy. Non oral treatments (rectal suppositories, nasal spray or injections) may be advisable when nausea and vomiting are severe. • In addition to its antiemetic effects,metoclopramide helps enhances absorption of oral medications.

• 2-Analgesics and Nonsteroidal Antiinflammatory Drugs • • Simple analgesics and (NSAIDs) are effective as first-line treatment for mild to moderate migraine attacks. • Aspirin, ibuprofen, naproxen sodium, tolfenamic acid. The combination of acetaminophen plus aspirin with caffeine or with short-acting barbiturate (butalbital) are also effective. • In general, NSAIDs with a long half-life are preferred as less frequent dosing is needed. • Rectal suppositories and intramuscular ketorolac are options for patients with severe nausea and vomiting.

• 2- Ergot Alkaloids and Derivatives • • Ergot alkaloids are useful for moderate to severe migraine attacks. They are nonselective 5HT1 receptor agonists. Venous and arterial constriction will occurs. • • Ergotamine tartrate is available for oral, sublingual, and rectal administration. • Oral and rectal preparations contain also caffeine to enhance absorption and potentiate analgesia. • Because oral ergotamine undergoes extensive first-pass hepatic metabolism, rectal administration is preferred. • Dosage should be titrated to produce an effective but sub-nauseating dose.

• • Dihydroergotamine (DHE) is available for intranasal and parenteral (IM, IV & SC) administration. • • Nausea and vomiting are common adverse effects of ergotamine derivatives. Pretreatment with an antiemetic should be considered with ergotamine and IV DHE therapy. DHE does not appear to cause rebound headache. • Symptoms of severe peripheral ischemia (ergotism) include cold, numb, painful extremities; continuous paresthesias; diminished peripheral pulses; and claudication. • Contraindications include renal and hepatic failure; coronary, cerebral, or peripheral vascular disease; uncontrolled hypertension; and women who are pregnant or nursing.

• 3-Serotonin Receptor Agonists (Triptans) • Sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan are appropriate first-line therapies for patients with moderate to severe migraine or as rescue therapy when nonspecific medications are ineffective. • These drugs are selective agonists of the 5HT1B and 5HT1D receptors. Relief of migraine headache results from normalization of dilated intracranial arteries

• Sumatriptan is available for oral, intranasal, and SC administration • Sumatriptan is available for oral, intranasal, and SC administration. • When compared with the oral formulation, SC administration offers enhanced efficacy and a more rapid onset of action (10 vs. 30 minutes). • Intranasal sumatriptan also has a faster onset of effect (15 minutes) than the oral formulation. • Approximately 30% to 40% of patients who respond to sumatriptan experience headache recurrence within 24 hours; a second dose given at the time of recurrence is usually effective. • Second-generation triptans (all except sumatriptan) have higher oral bioavailability and longer half-lives than oral sumatriptan.

and lack of response to one agent does not preclude effective • Clinical response to triptans varies among individual patients, and lack of response to one agent does not preclude effective therapy with another member of the class. • Side effects of triptans include paresthesias, fatigue, dizziness, flushing & warm sensations. • Up to 15% of patients report chest tightness, pressure, heaviness, or pain in the chest. Although the mechanism of these symptoms is unknown, a cardiac source is unlikely in most patients. • Contraindications include ischemic heart disease, uncontrolled hypertension, cerebrovascular disease, and hemiplegic migraine. • Triptans should not be given within 24 hours of ergotamine derivative administration.

• 4- Opioids • • Opioids and derivatives therapy should be closely supervised. It includes: • meperidine, oxycodone, hydromorphone • All should be 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. • 5- Glucocorticoids • • Corticosteroids may be an effective rescue therapy for status migrainosus, which is a severe migraine that may last up to 1 week.

• * for patient preference to limit the number of attacks. • Pharmacologic Prophylaxis of Migraine • administered on a daily basis to reduce the frequency, severity, and duration of attacks. • Prophylaxis should be considered in the: • * patient with recurring migraines • * frequent attacks requiring symptomatic medication more than twice per week • * symptomatic therapies that are ineffective, contraindicated, or produce serious side effects • * for patient preference to limit the number of attacks. • * when headaches recur in a predictable pattern (e.g., exercise-induced or menstrual migraine). Attacks occur >2-4 times per month Disability occurs > 3 days per month Duration of attack > 48 h

• drug selection is based on side-effect profiles and conditions of the patient, a trial of 2 to 3 months duration is necessary to judge the efficacy of each medication. • Only propranolol, timolol, valproic acid & topiramate (anticonvulsant) are approved by the FDA for migraine prevention. • Prophylaxis should be initiated with low doses and advanced slowly until a therapeutic effect is achieved or side effects become intolerable. • Prophylaxis is usually continued for at least 3 to 6 months after headache frequency and severity have diminished, and then gradually tapered and discontinued, if possible.

• 1) β-Adrenergic Antagonists • β-Blockers (propranolol, nadolol, timolol, atenolol & metoprolol) are the most widely used treatment for prevention of migraine. • Bronchoconstrictive and hyperglycemic effects can be minimized with β1- selective β-blockers. • β-Blockers should be used with caution in patients with asthma, heart failure, peripheral vascular disease, atrioventricular conduction disturbances, depression and diabetes.

• 2) Antidepressants • Amitriptyline appears to be a tricyclic antidepressant (TCA) of choice, but imipramine, doxepin,nortriptyline, and protriptyline have also been used. • TCAs are usually well tolerated at the lower 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.

• 3) Anticonvulsants • Valproic acid and divalproex sodium can reduce the frequency, severity, and duration of headaches by at least 50%. • The extended release formulation of divalproex sodium is administered once daily and is better tolerated than the enteric-coated formulation. • Topiramate is recently approved by the FDA for migraine prophylaxis. Dose is initiated at 25 mg/day and increased slowly to minimize side effects, which may include paresthesias, fatigue, anorexia, diarrhea, weight loss, difficulty with memory, and nausea. • 4) Calcium Channel Blockers • Verapamil provided only modest benefit in decreasing the frequency of attacks. It has little effect on the severity of migraine attacks. It is generally considered a second- or third-line prophylactic agent.

• 5) Methysergide • Methysergide is a semi synthetic ergot alkaloid that is a potent 5HT2 receptor antagonist. • Its use is limited by the occurrence of potentially serious retroperitoneal, endocardial, and pulmonary fibrotic complications that have occurred during long-term uninterrupted use. • It is reserved for patients with refractory headaches that do not respond to other preventive therapies. • • Methysergide is best tolerated when taken with meals. Side effects other than GI intolerance are many include insomnia, hallucinations, claudication, and muscle cramps.

• 6) A prophylactic use of Nonsteroidal Antiinflammatory Drugs • • NSAIDs are modestly effective for reducing the frequency, severity, and duration of migraine attacks, but potential GI and renal toxicity limit daily or prolonged use. • They may be used intermittently to prevent headaches that recur in a predictable pattern (e.g., menstrual migraine). Treatment should be initiated 1 to 2 days before the time of headache

THE MIGRAINE LIFESTYLE CONSISTENCY timing of meals, balance of diet –- don’t skip meals, mix of different food groups sleep --- don’t oversleep or undersleep caffeine – “minimum daily dose” of caffeine on a daily basis exercise – the more aerobic exercise the better

MIGRAINE AND PREGNANCY during the 2nd and 3rd trimesters of pregnancy There is no consensus or evidenced based approach to treatment of headache during pregnancy Regular small amounts of caffeine, magnesium supplementation are reasonable non-prescription alternatives The only adverse event that has been identified with triptans and pregnancy is a slightly increased risk of premature delivery….i.e. ok to use triptans in severe cases

Tension Headache Treatment & Management Various modalities are used : hot or cold packs, ultrasound, transcutaneous electrical nerve stimulation (TENS) , improvement of posture, trigger point removal , occipital nerve blocks, stretching, and relaxation techniques. Regular exercise,, balanced meals, and adequate sleep may be part of a headache treatment program .

medication analgisics (acetaminophen , tylenol ) NSAIDs (ibuprofen , naproxen ) TCA drugs as single dose at night . ASA barbiturates Antiemetics r sedative (promethazine, prochlorperazine , metochloperamide ) Ergot alkaloids and derivatives ( Ergotamine tartrate , dihydroergotamine )

Cluster Headache Treatment & Management Inhalation of 100% O2 for 10 – 15 minutes. Intranasal lidocaine/sumatriptane. Prophylaxis Ergotamine Prednisolone Verapamil Lithium Methysergide.

Prevention The patient should avoid known headache triggers to the extent possible. For example, disturbances in the sleep cycle. Strong emotions . excessive physical activity.

Thank you