1. PHARMACOTHERAPY - I PHCY 310
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
PHARMACOTHERAPY - I
PHCY 310
Lecture -13 Neurologic Disorders “Headaches” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

2. Course Outcome
Upon completion of this lecture the students will be able to
Understand the international classification and diagnosis of headache disorders,
Describe pathophysiology, precipitating factors, non-pharmacological, pharmacological and prophylactic treatment for migraine headache,
Recommend the treatment for patients with other classes of headache including medication overuse headache.

3. Pain in the head that is located above the eyes or ears, behind the head (occipital), or in the back of upper neck.
Diagnosis:
To place the headache into the most appropriate class within a headache classification system.
The main (and only adequate) classification is that of the International Headache Society (IHS).
Primarily based on clinical features of headaches rather than on assumption about etiologies or mechanisms of headaches.

4. International Classification of Headache Disorders, 2nd Edition (ICHD-2)
Part 1: Primary headaches 1) Migraine 2) Tension-type headache 3) Cluster headache and trigeminal autonomic cephalalgias
ICHD-III Beta is the latest classification with more types of classess like Migraine without aura
1.2 Migraine with aura
1.2.1 Migraine with typical aura
Typical aura with headache
Typical aura without headache
1.2.2 Migraine with brainstem aura
1.2.3 Hemiplegic migraine
Familial hemiplegic migraine (FHM)

5. International Classification of Headache Disorders, 2nd Edition (ICHD-2)
Part 2: Secondary headaches (headaches caused by another diagnosis)
5) Post-traumatic
6) Vascular disease
7) Other intracranial pathology (tumor, etc.)
8) Substances
9) CNS infection
10) Homeostatic disorders, such as hypertension, hypoxia
11) Cervicogenic, ocular, sinus related
12) Psychiatric

6. International Classification of Headache Disorders, 2nd Edition (ICHD-2)
Part 3: Cranial neuralgias, facial pain
13) Neuralgias and neuropathy

7. Clinical Characteristics:
The Clinician should know the 4 main clinical characteristics of the headache:
Quality (pressing, throbbing, etc.)
Intensity (mild, moderate, or severe)
Location (unilateral, bilateral, etc.)
Response (to routine physical activities)
Throbbing-pulsated or feel pain in a series of regular beats

8. Headache Symptoms That Suggest a Serious Underlying Disorder
“Worst” headache ever
First severe headache
Sub acute worsening over days or weeks
Abnormal neurologic examination
Fever or unexplained systemic signs
Vomiting precedes headache
Induced by bending, lifting, cough
Disturbs sleep or presents immediately upon awakening
Known systemic illness
Onset after age 55
A complete neurologic examination is an essential.
In most cases, examination should be followed by a computed tomography (CT) or a magnetic resonance imaging (MRI) study.

9. Headaches – Classification
For diagnostic and therapeutic purposes, it is useful to categorize headache into one of two major types on the basis of underlying etiology.
Primary
No identifiable and treatable underlying cause.
Eg. Migraine, Tension-type, and Cluster headaches
Secondary
Variety of organic causes such as trauma, cerebrovascular malformations, and brain tumors.

10. Migraine Headache
Usually developed 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 frontotemporal region and may radiate to the occiput and neck.
It may occur unilaterally or bilaterally.
Migraine headaches often are accompanied by nausea and vomiting and may last for up to 72 hours.

13. Migraine Headaches
These headaches usually are alleviated by relaxation in a dark room and sleep.
Migraine is more common in females than males.
Migraine headaches are divided into
Migraine without aura
Migraine with aura
The term, aura, refers to the complex of focal neurologic symptoms (e.g., alterations in vision or sensation) that initiate or accompany a migraine attack.
It may be precipitated by a variety of dietary, pharmacologic, hormonal, or environmental factors.

14. Pathophysiology
Alterations in cranial vessel diameter and blood flow as the primary cause of migraine.
An imbalance in activity of serotonin-containing neurons and/or noradrenergic pathways in brainstem nuclei that modulate cerebral vascular tone and nociception.
This imbalance may result in vasodilation of intracranial blood vessels and activation of the trigeminovascular system.
Serotonin (5-hydroxytryptamine, or 5-HT) is an important mediator of migraine.

15. Precipitating Factors
Food Triggers
   Alcohol    Caffeine/caffeine withdrawal    Chocolate   Citrus fruits, bananas, figs, raisins    Dairy products    Fermented and pickled foods    Monosodium glutamate(e.g.Chinese food, seasoned salt)    Nitrate-containing foods (e.g., processed meats)    Saccharin/aspartame (e.g., diet foods or diet sodas)    Sulfites in shrimp    Tyramine-containing foods    Yeast products

16. Precipitating Factors
Environmental Triggers    Glare or flickering 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 (e.g., prolonged over exertion)    Stress or post-stress

17. Precipitating Factors
Medications
   Analgesic overuse    Benzodiazepine withdrawal    Cimetidine    Decongestant overuse    Ergotamine overuse    Estrogen therapy    Indomethacin    Nifedipine    Nitrates    Oral contraceptives    Reserpine    Theophylline

18. Goals for Acute Migraine Treatment
Treat migraine attacks rapidly and consistently without recurrence
Restore the patient’s ability to function
Minimize the use of backup and rescue medications
Optimize self-care for overall management
Be cost-effective in overall management
Cause minimal or no adverse effects

19. Non-pharmacologic Treatment
Application of ice to the head and periods of rest or sleep, usually in a dark, quiet environment, may be beneficial.
Preventive management should begin with identification and avoidance of factors that provoke migraine attacks
Behavioral interventions (relaxation therapy, biofeedback, cognitive therapy) are options for patients who prefer nondrug therapy/when drug is ineffective or not tolerated.
Biofeedback-A training technique that enables a person to gain some element of voluntary control over autonomic body functions.

20. Pharmacologic Treatment
Pretreatment with antiemetics (e.g., prochlorperazine, metoclopramide)
15 to 30 minutes prior to abortive therapy/use of non-oral treatments (rectal suppositories, nasal spray, injections) advisable when nausea and vomiting are severe.
In addition to antiemetic effects, the prokinetic agent metoclopramide enhances absorption of oral medications.
Acute migraine therapies should generally be limited to 2 days/wk to avoid the development of medication misuse (or rebound) headache.

21. Analgesics and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
Simple analgesics and NSAIDs are effective treatment for mild to moderate migraine attacks.
Aspirin, ibuprofen, naproxen sodium, tolfenamic acid, and the combination of acetaminophen plus aspirin and caffeine shown consistent evidence of efficacy.
NSAIDs with a long half-life that prevent their frequent use are preferred.
Rectal suppositories and intramuscular ketorolac are options for patients with severe nausea and vomiting.

22. Ergot Alkaloids and Derivatives
Ergot alkaloids are non-selective 5-HT1 receptor agonists that constrict intracranial blood vessels
They inhibit the development of neurogenic inflammation in the trigeminovascular system.
Dihydroergotamine (DHE) is available for intranasal and parenteral (intramuscular [IM], intravenous [IV], subcutaneous [SC]) administration.

23. Ergot Alkaloids and Derivatives
Patients can be trained to self-administer DHE by the IM or SC routes.
Nausea and vomiting are common adverse effects of ergotamine derivatives.
Ergotamine is 12 times more emetogenic than DHE; pretreatment with an antiemetic should be considered with ergotamine and IV DHE therapy.

24. Serotonin Receptor Agonists (Triptans)
Sumatriptan, zolmitriptan, naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan.
Appropriate first-line therapy for patients with moderate to severe migraine.
These drugs are selective agonists of the 5-HT1B and 5-HT1D receptors.
Sumatriptan is available for oral, intranasal, and SC administration.

25. Serotonin Receptor Agonists (Triptans)
Naratriptan has the slowest onset of action (4 hours), but less side effects.
It is used for moderate migraine attacks and for patients who have low tolerance for side effects.
All triptans are contraindicated in patients with cardiac disorders, or sustained hypertension.

26. Serotonin Receptor Agonists (Triptans)
Side effects of triptans
Paresthesias (an abnormal sensation, as burning), fatigue, dizziness, flushing, warm sensations, and somnolence (excessive daytime sleepiness ).
Minor injection site reactions are reported with SC use, and taste perversion and nasal discomfort may occur with intranasal

27. Prophylactic Therapy
Indicated if migraine attacks are severe enough to interfere with patient's quality of life, or if the patient has 3 or more severe attacks per month. 1) Beta-blockers Propranolol has been the most studied beta-blocker. However, nadolol and atenolol may have fewer CNS side effects as they may cross the blood-brain barrier less than other beta-blockers. 2) Calcium Channel Blockers Verapamil is useful in migraine and cluster headache

28. 3) Tricyclic Analgesics
Amitriptyline, nortriptyline and doxepin act as analgesics at doses lower than those required for affective disorders.
4) Antiepileptic Drugs
1- Valproic acid and divalproex sodium are effective in migraine prophylaxis, but teratogenicity (neural tube defects) may occur.
2- Topiramate is helpful, but should be avoided in patients with renal stones and increased intraocular pressure.
Start topiramate at a very low dose of 25 mg and increase very slowly to avoid cognitive side effects.
3- Gabapentin is generally well tolerated and has few side effects or drug interactions.

29. Cluster Headaches
Recurrent headaches that are separated by periods of remission that last from months to even years.
During those periods when clusters of headaches are experienced, the headaches usually occur at least once daily.
In contrast to migraine headaches, cluster headaches are more common in males than females.

30. Tension-Type Headaches
A dull, persistent headache, occurring bilaterally in a hatband distribution around the head.
The headache is usually not debilitating and may fluctuate in intensity throughout the day.
Often occur during or after stress, but chronic tension-type headaches may persist for months even in the absence of recognizable stress.

31. Secondary Headache Disorders
Headache associated with head trauma, vascular disorders, central nervous system (CNS) infection (including HIV), or metabolic disorders.
Such headaches may develop suddenly, over a period of hours to days (acute headache), or more gradually over days to months (sub-acute headache).

32. Medication-overuse headache
It can result from overuse of analgesics, therefore:
- Nonopioid analgesics should be used < 15 days / month.
Opioids and combinations should be used < 10 days / month.
Triptans should be used less than 10 days / month.
Most patients with medication-overuse headache will improve in days or a few weeks with the discontinuation of these medications.

33. Key points in Migraine Management
Initiate therapy for acute migraine with simple analgesia, including paracetamol, aspirin and nonsteroidal anti-inflammatory drugs.
Always consider CV risk, GI and renal adverse effects when using aspirin, conventional and COX-2 selective NSAIDs.
Escalate treatment to migraine-specific drugs (5HT1 agonist [naratriptan, sumatriptan, zolmitriptan] or ergot alkaloid [ergotamine, dihydroergotamine]) if simple analgesia fails.

34. Over-the-counter combination analgesics, codeine and other opioids are not recommended for managing migraine.
They can worsen symptoms of nausea and vomiting and impede the absorption of other medications.
The use of tramadol in chronic pain management has been well established but its efficacy in migraine is not proven.
Consider preventive measures, including prophylactic drug treatment, and behavioural or complementary approaches for those who suffer 2-3/> severe migraines/month.

35. Consider prophylactic therapy in patients who continue to experience more than 2–3 acute attacks of migraine per month.
The initial choice of drug will depend on individual comorbidities and the adverse-effect profile of the drug.
Use only one preventive agent at a time for migraine and increase the dose gradually to the lowest effective dose.
Propanolol and metoprolol are considered first-line in migraine prophylaxis, unless contra-indicated.

36. Case
Lesley presents to her GP with a 24-hr history of unilateral severe throbbing headache associated with photophobia, nausea and vomiting (3 times in 24 hrs).
Lesley’s initial self-management is aspirin (soluble) 900 mg and metoclopramide 10 mg orally with a repeated dose of aspirin 600 mg every 4 hours.
Lesley has had no symptom relief from the aspirin.
Lesley has been unable to attend work or care for her children and states that she rarely has such a severe attack.