Treatments for Tension Headache and Chronic Daily Headache

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Chronic Daily Headache

Release Date: 03/30/2012

Expiration Date: 03/30/2015

FACULTY:

L Howe, BS, MS

FACULTY AND ACCREDITOR DISCLOSURE

STATEMENTS:

L. Howe MS has no actual or potential conflict of interest in relation to this program.

ACCREDITATION STATEMENT:

Pharmacy

PharmCon Inc is accredited by the Accreditation Council for Pharmacy

Education as a provider of continuing pharmacy education.

Program No.: 0798-0000-17-031-H01-P

Credits: 2 contact hour, 0.2 CEU

Nursing

Pharmaceutical Education Consultants, Inc. has been approved as a provider

of continuing education for nurses by the Maryland Nurses Association which is

accredited as an approver of continuing education in nursing by the American

Nurses Credentialing Center’s Commission on Accreditation.

Program No.: N-756

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This accredited program is targeted nurses and pharmacists practicing in hospital and

community pharmacies. Estimated time to complete this monograph and posttest is 120

minutes.

DISCLAIMER:

PharmCon, Inc does not view the existence of relationships as an implication of bias or

that the value of the material is decreased. The content of the activity was planned to be

balanced and objective. Occasionally, authors may express opinions that represent

their own viewpoint. Participants have an implied responsibility to use the newly

acquired information to enhance patient outcomes and their own professional

development. The information presented in this activity is not meant to serve as a

guideline for patient or pharmacy management. Conclusions drawn by participants

should be derived from objective analysis of scientific data presented from this

monograph and other unrelated sources.

Program Overview:

To provide nurses and pharmacists with an understanding of the prevalence and

incidence of tension headaches.

OBJECTIVES:

After completing this program, participants will be able to:

Describe the current knowledge of the pathophysiology of tension0type and

chronic daily headache

Describe the symptoms of an episodic tension-type headache (TTHA)

List the criteria for TTHA and chronic daily headache

Describe non-pharmacologic and behavioral therapies that may treat or prevent

headaches

List first-line acute treatments for headaches

List first-line prophylactic treatments for headaches

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Howe-Headaches Page 1

Types of Headache

Headache is a very common problem that affects many people every year. Approximately 14,000 patient visits to health care professionals occur each year due to headache

complaints.1 Over 90% of men and women have one or more headaches each year, with 4.5

million Americans experiencing recurrent headaches.2

Headache is divided into two main types: primary and secondary. Primary headaches, those without an apparent underlying disease, are further classified into migraine, tension-type, and cluster headaches. Secondary headaches are those that can be traced to an organic cause and are considered a symptom to be managed as the underlying cause is treated. Treatments for tension-type headaches and the management of chronic daily headaches are the subjects of this monograph.

Tension-type headache (TTHA)

Tension-type headaches are common, with over 95% of women and 90% of men having experienced this type of headache at least once.1 Women are slightly more likely to

experience TTHAs than men, and the headaches themselves may be episodic or chronic. Tension-type headaches have been categorized into two groups by the International Headache Society: those with or without pericranial tenderness.2 TTHAs can be further

classified by cause; examples include temporomandibular joint dysfunction, psychosocial stress, and analgesic overuse.

Pathophysiology

Even though most people know how a tension-type headache feels, no one really knows how or why they happen. TTHA was originally thought to be caused by long-term muscle contraction of the neck, jaw, scalp, or facial muscles; but more recent theories suggest that

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Howe-Headaches Page 2 the sustained muscle contraction occurs as a secondary outcome of a more centralized disturbance. One theory is that altered levels of serotonin, substance P, and neuropeptide Y in the serum or platelets are responsible for the headache.3

Data does not support the belief that stress or other psychological factors cause tension headaches, but stress, sleep deprivation, hunger, and eyestrain may make the headache symptoms worse. A group of physical conditions may also lead to TTHAs including

degenerative joint disease, trauma to the head or neck, poor posture, and

temporomandibular joint dysfunction. Anyone over 50 is also more susceptible to excessive muscle contractions and TTHAs because of arthritis of the neck and jaw, poor posture, or stress.3

Symptoms / Diagnosis

The pain of a TTHA is characterized by intermittent or persisting bilateral pain and is

described as squeezing pressure or a band of pressure around the head. Most people report pain in the frontal, temporal, or occipital areas of the head, but location and intensity often vary during the attack and among patients. Tightness of the neck and shoulders is also commonly reported. A headache attack may last a few hours or up to several days, and, for some patients, may last up to several months.3 Migraine headache symptoms, including

aura, nausea, photophobia, phonophobia and severe disability, are not typically seen with TTHA.

The diagnosis of most headaches is based on patient history and a physical exam. While there is limited need for imaging or laboratory tests, a comprehensive assessment can rule out comorbid conditions that may be exacerbating the headache. Fever, stiff neck, evidence of recent trauma, visual field disturbances, papilledema, or motor and sensory neurologic deficits all signal underlying problems that warrant more specific investigations. Patients

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Howe-Headaches Page 3 with frequent TTHAs should be evaluated for migraine as some data suggests that TTHAs may actually be low intensity migraines in some patients.1

The criteria for diagnosis of episodic tension-type headache include4:

 Headache occurs on fewer than 15 days per month

 Headache lasts 30 minutes to 7 days

 Headache shows at least two of the following characteristics: o Pressing/tightening (but not pulsating) quality

o Mild to moderate intensity (may inhibit but does not prohibit activities) o Bilateral location

o Not aggravated by routine physical activity

 Both of the following are true: o No nausea or vomiting

o No photophobia and phonophobia (or only one is present)

 Organic disorder is ruled out

Treatment of existing headache

The goals of treatment are to reduce the severity of symptoms and the frequency of TTHAs, to decrease any related disability, and to minimize medication use to prevent progression to chronic daily headache. Non-pharmacologic self-care such as stress avoidance, stretching, warm packs or relaxation techniques can be very helpful in reducing headache pain. When TTHAs are severe or very frequent, professional interventions such as manipulation,

physical therapy, local injections or biofeedback training may be considered.3 Daily or

near-daily use of analgesics can lead to Medication Overuse Headache, which can compound the patient’s problem and make it worse.3

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Howe-Headaches Page 4 First line medications for tension-type headache include over-the-counter acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, naproxen, and ketoprophen.

Acetaminophen (Tylenol)5

Acetaminophen is a para-aminophenol analgesic that shows antipyretic activity similar to aspirin but without aspirin’s peripheral anti-inflammatory activity or effects on platelet function. It is effective at relieving acute and chronic pain and is chosen over aspirin due to its fewer hematologic, GI, and renal effects. Acetaminophen has a good safety record but its misuse is the number one cause of acute hepatic failure in the U.S. In January 2011, the FDA asked manufacturers of prescription combination products that contain acetaminophen to limit the amount of acetaminophen to no more than 325 mg in a single tablet or capsule. The FDA also required the manufacturers to update labels of prescription drug products that contain acetaminophen to include a warning of the potential risk for severe liver injury and another warning of the potential for allergic reactions (swelling of the face, mouth and throat, difficulty breathing, itching, or rash).

Mechanism of action

Acetaminophen is thought to act primarily in the central nervous system to increase the pain threshold by inhibiting both isoforms of cyclooxygenase (COX-1 and COX-2), a group of enzymes that take part in the production of prostaglandins. Acetaminophen does not inhibit cyclooxygenase in peripheral tissues and lacks the ability of other NSAIDs to reduce

peripheral inflammation. It may also act to inhibit chemical mediators that sensitize pain receptors to stimulation. Acetaminophen also blocks the effects of fever-inducing substances on the hypothalamus by inhibiting prostaglandin synthesis.

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Howe-Headaches Page 5 An overdose of acetaminophen will lead to hepatotoxicity and possible acute renal failure; habitual ingestion may also lead to hepatotoxicity or chronic analgesic nephropathy. All three conditions are due to the formation of N-acetyl-para-benzoquinoneimine (NAPQI) in the liver and to a lesser extent, in the kidneys. NAPQI binds to tissue macromolecules and leads to cell necrosis.

Pharmacokinetics/pharmacodynamics

Acetaminophen is rapidly absorbed from the GI tract after an oral dose and peak concentrations are reached within 30-60 minutes. It is approximately 10-25% protein bound. About 25% of the dose is subject to first-pass metabolism by the liver and eventually 85-90% is metabolized by the liver through glucuronidation and sulfate conjugation. The remaining 10-15% undergoes oxidation to produce NAPQI, which is

eventually excreted into urine as thioether metabolites. Excess NAPQI may be formed when acetaminophen is given at the same time as liver enzyme-inducing agents such as

rifampicin, rifabutin, caramazepine, oxcarbasepine, phenytoin, barbiturates, primidone, topiramate, non-nucleoside reverse transcriptase inhibitors, and ritonavir boosted protease inhibitors. In addition, fasting shifts the metabolic pathway towards oxidation and a greater production of NAPQI. Acetaminophen’s elimination half-life is 2-4 hours in adults with normal liver function, and more than 90% of the initial dose is eliminated in the urine within 24 hours.

Dosages and formulations

Tylenol is supplied as 325 mg tablets, extra strength tablets, extra strength caplets, extra strength geltabs, extra strength gelcaps, extra strength rapid-release gels, extra strength GoTabs, and liquid.

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Howe-Headaches Page 6 The recommended dose of regular release formulations for adults and children older than 12 years for temporary relief of headache is 325-650 mg every 4-6 hours as needed, not to exceed 4 g per day. For children less than 12 years old, the recommended dose is 10-15 mg per kilogram of weight every 4-6 hours not to exceed 5 doses in 24 hours. For neonates, the recommended dose is 10-15 mg per kilogram of weight every 6-8 hours as needed.

The recommended dose of extended release formulations for adults and children older than 12 years is 650-1300 mg every 8 hours as needed with the total daily dose not to exceed 6 extended-release tablets or 4 g per day. Extended release tablets are not recommended for self-medication in children under 18 years of age.

Contraindications

Acetaminophen should not be given to patients with known hypersensitivity to

acetominophen or any of its excipients. Patients with kidney impairment should not take acetaminophen on a chronic basis but can use it for episodic pain relief. Patients with G6PD deficiency should be monitored to prevent overdose since acetaminophen can cause

hemolysis. Acetaminophen should be used with caution in patients with salicylate hypersensitivity.

Complicating factors and adverse effects

The half-life of acetaminophen may be prolonged in patients with liver disease.

Acetaminophen metabolites (although not the unchanged drug) can accumulate in patients with kidney disease. Acetaminophen should not be used for self-medication by patients for longer than 10 days in adults or 5 days in children. Smoking may increase the generation of NAPQI and increase the risk of liver damage. Acetaminophen crosses into breast milk and should be used with care in breastfeeding mothers.

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NSAIDS (aspirin, ibuprofen, naproxen, ketoprophen)6,7,8,9

Aspirin and other NSAIDs are widely used as analgesics and for their anti-inflammatory and anti-pyretic effects. They all have been found to be effective first-line medications for treating TTHAs, although few actual studies have been done in this area and few data exist to offer guidance about the most effective choices.1 All NSAIDs carry an increased risk of

serious cardiovascular and gastrointestinal events.

Aspirin6

Aspirin, the salicylic ester of acetic acid, is used for its analgesic, anti-inflammatory, antipyretic, and antithrombic activity. Introduced in 1899, it was approved by the FDA in 1939.

Mechanism of action

Prostaglandins are produced in the body and act to promote inflammation, pain and fever, support the blood clotting activity of platelets and protect the stomach lining from the effects of acid. The enzyme cyclooxygenase (COX) plays an active role in the production of prostaglandins and is present in two isoforms (COX-1 and COX-2). Both isoforms produce prostaglandins, but only the COX-1 form is involved in platelet support and protection of the stomach lining. By inhibiting the activity of the COX enzymes, NSAIDS reduce the amount of prostaglandin present and, as a result, inflammation, pain, and fever are reduced. The reduction of the COX-1 isoform may also reduce blood clotting and cause stomach ulcers. Aspirin differs from other NSAIDs in its mechanism of action by being 170 times more potent in inhibiting COX-1 than COX-2 and by irreversibly inhibiting both COX isoforms.

Pharmacokinetics/pharmacodynamics

Aspirin is absorbed from the stomach and upper intestine via passive diffusion as

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Howe-Headaches Page 8 The absorption rate depends on gastric and intestinal pH, gastric emptying time, the

presence of food, and the formulation. Aspirin is absorbed quickest when formulated as effervescent or soluble tablets and in declining speed as uncoated or film-coated tablets, enteric coated tablets, and extended release formulations. Food decreases the rate but not the extent of absorption; a higher pH increases absorption. Time to peak aspirin

concentration is 15-240 minutes depending on the formulation; time to peak salicylate levels occur in 30-60 minutes for effervescent tablets, 45-120 minutes for film-coated tablets, 4-12 hours for extended release tablets, and 8-14 hours for enteric coated tablets. Aspirin is rapidly hydrolyzed to salicylic acid in the liver and its half-life is 15-20 minutes. The elimination half-life of salicylic acid varies with the dose; a low dose will have an elimination half-life of 2-3 hours but it can rise to 15-30 hours after a high dose. Over 80% of the salicylic acid is excreted from the kidneys within 24-72 hours─ 10% as free salicylic acid, 75% as salicyluric acid, 10% as salicylic phenolic and 5% as acyl glucuronides and 1% as gentisic acid.

Dosages and formulations

The recommended dose of aspirin for headache in adults or adolescents is 325-650 mg every 4 hours as needed up to a maximum of 4 g per day. The recommended dose for children is 10-15 mg every 4-6 hours not to exceed 4 g per day.

Contraindications

Children and adolescents who have or who are recovering from chicken pox or flu-like symptoms should not use aspirin to avoid the risk of developing Reye’s syndrome. Patients with acetaminophen hypersensitivity may have an increased risk of aspirin hypersensitivity. Women in the third trimester of pregnancy should not use aspirin, and it should be used during the first two trimesters only if it is clearly needed. Aspirin should be used with

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Howe-Headaches Page 9 caution or not at all in patients with GI disease or previous NSAID-induced bleeding,

hemophilia, and other blood diseases. Salicylates are excreted in breast milk.

Complicating factors and adverse effects

Aspirin should be used with caution in patients with liver or renal impairment and in elderly patients who are more susceptible to decreased renal function. Adverse effects include GI disturbances, tinnitus and hearing loss, allergic reactions, liver disturbances, Reye’s syndrome, and platelet dysfunction.

Ibuprofen7

Unlike aspirin, ibuprofen is a member of the propionic acid class of medications, a group that is usually better tolerated than aspirin. It is a mixture of two isomers, only one of which has been shown to have clinical usefulness for treatment of rheumatoid arthritis,

osteoarthritis, dysmenorrhea, ankylosing spondylitis, gout, psoriasis, fever reduction, and mild to moderate pain. It was approved by the FDA in 1974.

Pharmacokinetics/pharmacodynamics

The volume of distribution of ibuprofen is dependent on patient age and body temperature. It is highly protein bound (90-99%) up to 20 mcg/ml when protein binding becomes

saturated and linear. It is metabolized through oxidation in the liver to inactive metabolites. The plasma half-life is 2-4 hours and it is excreted in the urine; 50-60% is excreted as inactive metabolites; and 10% as unchanged drug. Its bioavailability is approximately 80%, but its time to peak concentrations is based on formulation: tablets - 120 minutes, and chewable tablets - approximately 62 minutes. Food has a minimal effect on bioavailability.

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Howe-Headaches Page 10 Ibuprofen is available over the counter in 200 mg caplets, capsules, and tablets. The

recommended dose for headache in adults and adolescents is 200-400 mg every 4-6 hours not to exceed 1200 mg per day. Self-treatment should not exceed 10 days unless directed by a physician. Elderly patients should use the lowest possible dose that is effective for the shortest duration.

Ibuprofen is also available in formulations for children in 100 mg caplets or chewable tablets, 50 mg chewable tablets, 100 mg/5 ml suspension, and 40 mg/ml concentrated drops. The recommended dose for children for headache is based on age and weight:

Children 6—8 years or weighing 48—59 lbs: 2 tablets (200 mg) every 6—8 hours as

needed.

Children 9—10 years or weighing 60—71 lbs: 2.5 tablets (250 mg) every 6—8 hours

as needed.

Children 11 years or weighing 72—95 lbs: 3 tablets (300 mg) every 6—8 hours as

needed.

50 mg chewable tablets or 100 mg/5 ml suspension:

Children 2—3 years or weighing 24—35 lbs: 1 teaspoonful (5 ml) or 2 chewable

tablets (100 mg) every 6—8 hours as needed.

Children 4—5 years or weighing 36—47 lbs: 1.5 teaspoons (7.5 ml) or 3 chewable

tablets (150 mg) every 6—8 hours as needed.

Children 6—8 years or weighing 48—59 lbs: 2 teaspoons (10 ml) or 4 chewable

tablets (200 mg) every 6—8 hours as needed.

Children 9—10 years or weighing 60—71 lbs: 2.5 teaspoons (12.5 ml) or 5 chewable

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Children 11 years or weighing 72—95 lbs: 3 teaspoons (15 ml) or 6 chewable tablets

(300 mg) every 6—8 hours as needed.

Self-treatment should not exceed 3 days unless directed by a physician, and it should not be used more than 4 times a day.

Contraindications

Ibuprofen should be used with caution in patients with asthma, GI diseases, liver disease, kidney disease, cardiovascular disease and hypertension, hematological diseases, and in pregnant and breastfeeding women.

Complicating factors and adverse effects

Gastrointestinal complaints are the most common adverse effects followed by esophagitis, pancreatitis, tinnitus, renal failure, and increased blood pressure, among others.

Naproxen sodium8

Naproxen is also a member of the propionic acid class and is used as an analgesic and antipyretic in adults and children. Anaprox was approved by the FDA as an over-the-counter drug in 1994.

Pharmacokinetics/pharmacodynamics

Naproxen is administered as an acid or a sodium salt and is more than 99% bound to albumin. It has a plasma half-life of 12-17 hours and is metabolized in the liver to inactive metabolites. Approximately 95% is excreted in the urine with less than 1% as unchanged naproxen, less than 1% as 6-O-desmethyl naproxen, and 66-92% as their gluconurides or other conjugates. A very small amount, 3% or less, is excreted in feces. When administered orally, naproxen is completed absorbed from the GI tract with the sodium form absorbed

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Howe-Headaches Page 12 more rapidly than the acid form. Pain relief may be experienced within 30 minutes after taking naproxen sodium. The rate of absorption, but not the extent, is reduced when taken with food. After taking naproxen sodium in tablet form, peak plasma concentrations are achieved in 2-4 hours.

Dosages and formulations

Naproxen sodium (more appropriate for quick headache relief than the slower acting acid form of naproxen) is available as Anaprox 275 mg and 550 mg tablets. The recommended dose for treatment of mild to moderate headache pain in adults is 550 mg initially followed by 275 or 550 mg every 6-8 hours as needed. The maximum dose should not exceed 1375 mg on day one or 1100 mg per day on subsequent days. Elderly patients should use a lower dose and only use naproxen sodium if other therapies have failed.

Contraindications

Patients should not use naproxen if they have a hypersensitivity to salicylate or NSAIDs or are recovering from coronary artery bypass graft surgery. Naproxen should be used with caution in patients with liver disease, hypertension, congestive heart failure, kidney disease, hematological diseases including anemia, or in children.

Complicating factors and adverse effects

Chronic use of naproxen can result in GI disturbances. Naproxen crosses into the placenta and is excreted in breast milk; it should be avoided in breastfeeding women and during late pregnancy.

Ketoprofen 9

Similar to ibuprofen, ketoprofen is another NSAID of the propionic acid chemical class that exhibits both analgesic and antipyretic activity.

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Howe-Headaches Page 13 Pharmacokinetics/pharmacodynamics

Ketoprofen is absorbed rapidly and almost completely from the GI tract. Bioavailability is approximately 90% and peak plasma concentrations are reached in 1.2 hours in fasting state with immediate-release formulations. Food or milk may slow the rate of absorption but not the extent. The half-life of ketoprofen from immediate-release tablets is approximately 2.1 hours, and it is more than 99% protein bound. Extensive metabolism occurs in the liver to inactive metabolites. Excretion is primarily in the urine within 12-24 hours and in the form of metabolites; less than 1% is excreted as unchanged drug. A small amount of the original dose, 1-8%, is eliminated in feces, and clearance is complete in 24-48 hours.

Dosages and formulations

Ketoprofen is available in 25 mg, 50 mg, and 75 mg capsules. The recommended dose for treatment of headache is 75 mg 4 times per day. In elderly, small, or debilitated adults, the recommended initial dose is 25-50 mg three times per day titrated to a maximum of 300 mg per day. The recommended dose for self-medication of headache is 12.5 mg every 4-6 hours. If there is no relief after 1 hour, an additional 12.5 mg may be taken with a

maximum dose not to exceed 75 mg per day. Self-medication should not exceed 10 days.

Contraindications

Patients should not use ketoprofen if they have a hypersensitivity to salicylate or NSAIDs or are recovering from coronary artery bypass graft surgery. Ketoprofen should be used with caution in patients with liver disease, kidney disease, hypertension, congestive heart failure, hematological diseases and anemia, and in pregnant or breastfeeding women.

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Howe-Headaches Page 14 Chronic use of ketoprofen can result in GI disturbances. Generic capsules may contain lactose.

Aspirin or acetaminophen combined with caffeine 10 ,11

Caffeine is included with NSAIDs to increase their analgesic effect, although data about this effect are lacking. Data exist that indicate caffeine may increase the bioavailability of some analgesics, but it has no analgesic properties on its own. Frequent use of NSAIDs in

combination with caffeine may precipitate chronic daily headaches.1

Opioid analgesics (butalbital, meperidine, others including combinations)

Opioids are predictably effective and safe analgesics, but misperceptions about addictions, side effects and the stigma of abuse create barriers to their more extensive use.12

Barbiturate-containing analgesics should be used with caution for treatment of headache because they have a strong tendency to induce rebound and medication overuse headaches or chronic daily headaches.1

Prophylactic treatment of tension-type headache

Patients who have more than 15 headaches per month are candidates for a prophylactic regimen.1 In addition to the over-the-counter NSAIDS discussed above, tricyclic

antidepressant (TCA) and selective serotonin reuptake inhibitor (SSRI) at the lowest effective doses are commonly used to prevent TTHAs.3

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Howe-Headaches Page 15 Tricyclic antidepressants have been shown to be effective at reducing the frequency and intensity of TTHAs and amitriptyline has been the most studied and prescribed in this group.1 Potential side effects such as fatigue and weight gain may limit their use, however.3

Amitriptyline (Tryptanol™, Vanatrip®)13, 14, 15

Amitriptyline is a tertiary amine tricyclic antidepressant. The use of antidepressants for tension headache prophylaxis has not been approved by the FDA, but studies have shown that they can be effective, especially in the case of amitriptyline.14

Mechanism of action

The mechanism of action of tricyclic antidepressants is not well understood, but it is thought that they decrease the reuptake of norepinephrine and serotonin.15

Pharmacokinetics/pharmacodynamics

Amitriptyline is usually well absorbed from the GI tract, but this varies among individuals. It may take several weeks before the full antidepressant effects are felt, but adverse effects may appear immediately after the first dose. Peak plasma concentrations are reached within 2-12 hours after administration, and the effects are long lasting. Amitriptyline is

metabolized in the liver to nortriptyline, which crosses the blood-brain barrier and the placenta and is excreted in breast milk. Between 25-50% of a single dose is excreted in the urine within 24 hours, and a small amount of excretion occurs in the feces.

Dosages and formulations

Amitriptyline is available in 10 mg, 25 mg, 50 mg, 75 mg, 100 mg and 150 mg tablets. The recommended dose for TTHA prophylaxis in adults is 10-75 mg at night for 1-3 months.

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Howe-Headaches Page 16 Amitriptyline should not be used with patients who are in the acute recovery phase after myocardial infarction, who have any cardiac disease, or who are taking MAOI therapy (or within 14 days of discontinuing treatment with an MAOI). Discontinuation of amitriptyline, especially after prolonged high doses, should be gradual to avoid symptoms of cholinergic rebound. Amitriptyline should be used with caution in patients with hematological disease, alcoholism, asthma, cardiac conduction defects, glaucoma, diabetes, GI disease, or BPH. Amitriptyline should not be administered to children, and administered with caution to elderly patients and breastfeeding mothers.

Complicating factors and adverse effects

A long list of adverse effects includes anxiety and other psychological symptoms, orthostatic hypertension and other cardiac effects, sleep disturbances and drowsiness, weight gain, tremor, seizures, blurred vision, sexual dysfunction, and serotonin syndrome.

Selective Serotonin Reuptake Inhibitors (SSRIs)

As a group, SSRIs have shown some effectiveness at preventing TTHAs, but they are not as effective as amitriptyline.1 The advantage of using them is their lower rate of medication

side effects, but they are not approved by the FDA for this indication.1

Non-pharmacologic therapies Acupuncture

Studies have shown that acupuncture provides significant pain relief for some patients, although there is no consensus in the clinical literature. A 2005 meta-analysis of controlled studies indicated a strong trend in favor of acupuncture as a prophylactic TTHA treatment. 16

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Howe-Headaches Page 17 Behavioral intervention can help patients identify and eliminate behaviors that may be aggravating the headache, whether combined with other therapies or on its own. It may be as simple as educating the patient about headache disorders or, if the patient is

experiencing anxiety and depression, cognitive behavioral therapy (CBT) may be indicated. Biofeedback and relaxation training can be especially useful in patients with typical signs of anxiety such as cold hands and feet. Behavioral treatments have the added advantage of helping patients feel involved in their own treatment plan, which will likely enhance compliance and satisfaction with treatment.

A large amount of evidence exists that behavioral treatments are effective in managing headache; in the case of tension-type headaches, patients have been able to reduce their headache activity by almost 50%.17 A meta-analysis of studies shows a 35-55% reduction in

headaches with behavioral treatments and reductions in headache frequency and severity that are comparable to typically used pharmacologic treatments.1

Physical therapy (posture training, ice packs, massage)

Rigorous studies of the use of these therapies are lacking but posture training, ice packs, and massage may be useful in preventing TTHAs and should be tried.1

Chronic daily headache

The definition of chronic daily headache is the presence of headache on more than 15 days per month for more than three months.18 Chronic daily headache may occur as a chronic

tension-type headache (TTHA) or a combination of tension-type and migraine, which is the more common form seen in clinics. Since there is no actual class called combination

headache in standard headache classification, physicians must diagnose both headache types when a combination is suspected. Chronic daily headache most often occurs in

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Howe-Headaches Page 18 patients who have episodic migraine headaches to start but who gradually develop a near-daily headache over a period of years. Patients with chronic migraine (CM) headaches and medication overuse headaches (MOH) are the most common types of chronic daily

headache, and the remainder of this monograph will focus on these disorders.

Approximately 2% of the population experiences chronic migraine and females are more likely to develop CM than males at a 3:1 ratio.18 In addition, over half of patients with CM

experience sleep and mood disorders such as anxiety and depression, which should be addressed along with the headache condition.18

Medication overuse headaches occur in an estimated 1.4% of the population. 18 Of patients

with chronic daily headache, approximately 18-33% overuse acute headache medications, which indicates that chronic daily headache may occur without medication overuse, and medication overuse does not necessarily lead to medication overuse headache. 18 The

implication of this last statement is that tapering and discontinuing the medication does not always restore a patient to episodic or pre-medication headache patterns.

Pathophysiology

Medication overuse headache, also called rebound or medication-induced headache, may occur from the frequent use (more than 10 days per month) of analgesics, especially opiate compounds and those containing caffeine or butalbital. The pain medications may

themselves induce and maintain the daily headache syndrome. Daily migraine headaches can occur from the frequent use of ergotamine tartrate or any of the triptan drugs. Risk factors for the development of chronic migraines (CM) include obesity, a history of frequent headache (more than one per week), caffeine consumption, and overuse of headache medications (used more than 10 days per month) including analgesics, opioids, ergots, and triptans.18

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Howe-Headaches Page 19 The actual pathogenesis of medication overuse headache is unclear. The leading theory is that the sensitivity of the central trigeminal pathway is intensified by a medication-induced impairment of the inhibition of neuronal excitability.

Symptoms / Diagnosis

Chronic migraine and chronic tension-type headaches are characterized by individual headache episodes that last longer than four hours with distinct periods without headache, although sometimes patients experience a continuous background headache with periods of severe and disabling headaches superimposed. Medication overuse headache is described as a diffuse, bilateral, almost daily headache that may be exacerbated with mental or physical exertion and may be associated with depression, restlessness, forgetfulness, and sometimes nausea.

Diagnosis is by comparison with standard criteria. Chronic migraine is diagnosed when a patient experiences headache for 15 days per month or more for longer than three months, of which at least 8 days meet the International Headache Classification (ICHD-2)19 criteria

for migraine without aura, or relief is achieved with triptan or ergot. Chronic tension-type headache is diagnosed when a patient reports bilateral, non-throbbing headaches of mild-moderate severity with no migraine symptoms.

Medication Overuse Headache is diagnosed when headache is present on 15 days per month and there is regular (longer than 3 months) overuse of one or more drugs that are taken for acute or symptomatic treatment of headache. 18

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 Ergotamine, triptans, opioids, and combination analgesics taken more than 10 days per month

 Simple analgesics taken 15 days or more per month

 Total exposure of all acute medications greater than 10 days per month.

In addition, the following criteria will depend on which drugs are being overused:

 The headache has developed or grown markedly worse during the period of medication overuse

 Headache resolves or reverts to previous pattern within two months after discontinuation of overused medication.

Analgesics, opioids, ergotamines and triptans, alone or in combination are the drugs most often implicated in medication overuse headaches. Overuse of triptans can trigger MOH in the shortest time (1.7 years), ergots in 2.7 years, and analgesics in 4.8 years; the duration of withdrawal symptoms and recidivism rate is also shortest for triptans and longest for analgesics.18

If a patient reverts to an episodic headache pattern within two months of withdrawing the drug, MOH is diagnosed. If the patient continues to experience headache on more than 15 days per month after drug withdrawal, an alternative diagnosis for the chronic daily headache is sought.

Treatment for medication overuse headache

Treatment of medication overuse headache is often not easy or straightforward. It typically requires both nonpharmacologic therapy and acute and prophylactic headache treatment. 18

Lifestyle changes such as limiting caffeine consumption, quitting smoking, exercise and establishing regular meal times and bedtimes can be helpful for some patients. Since more

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Howe-Headaches Page 21 than half of patients with MOH also experience depression, anxiety, and sleep disturbances, these disorders must be treated at the same time. Relaxation training and biofeedback may help those for whom stress is a headache trigger. 18

The second step in treatment is the removal of the overused acute medications; withdrawal may be sudden except for barbiturates or opioids. Butalbital should be tapered over 2-4 weeks. If the patient is at risk for withdrawal syndrome, the patient may have 30 mg of phenobarbital twice per day for two weeks, followed by 15 mg twice per day for 2 weeks. Opioids should be tapered over 2-4 weeks and if there is a risk of withdrawal syndrome, the patient may have clonidine for 1-2 weeks. Patient with marked withdrawal symptoms and headache may be given 60-100 mg prednisone for 5 days, which has been shown to be effective as a transitional, short-term treatment. 18

If headaches are severe during the transitional period, NSAIDs may be given no more often than three days per week. Intranasal or sub-cutaneous or intramuscular injections of dihydroergotamine may be used for migraine headaches during the transitional period. Nausea and vomiting may be relieved with anti-emetics such as metoclopramide, prochlorperazine, or ondansetron.

When to begin preventive medications is controversial. It has long been believed that because the daily headache may resolve or improve as the overused medication is withdrawn, preventive medications should not be started until this strategy proves inadequate. Some recent studies, however, have shown that treatment with Botox and topiramate in patients with chronic migraine or medication overuse headaches reduces headache frequency. This, in turn, leads to a reduction in the consumption of acute medications even when overused acute medications are not actively withdrawn. 18

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Howe-Headaches Page 22 Unfortunately, studies indicate that a high percentage of patients with MOH relapse, up to 41% within the first year and 45% after four years; and only one-third of patients treated for MOH refrained from medication overuse at the end of 4 years of follow-up. 18

Medications for prevention of chronic migraine or medication overuse headache

Amitriptyline (see above) and the SSRI, fluoxetine, have both shown effectiveness in preventing episodic migraine and are used extensively to prevent chronic migraine and medication overuse headache. Gabapentin has been shown to be effective at preventing chronic daily headache18; and, while there have been few actual studies, divalproex sodium

has been used in clinical practice effectively to treat episodic migraine and for migraine prevention. Studies have demonstrated that topiramate was effective and achieved good reductions in migraine frequency. 18 Botulinum neurotoxin type A has been evaluated in

placebo-controlled trials and results have been mixed and more studies are underway. 18

Fluoxetine HCL (Prozac®, Sarafem®, Selfemra™)20

Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is the first SSRI approved in the US for depression. Even though it has not been approved by the FDA for use as a preventive treatment for chronic migraine, studies indicate that subjects treated with fluoxetine had significant improvements in headache status, mood, and headache frequency. 21

Mechanism of action

The mechanism of action of SSRIs is not fully understood, but it is believed that they

enhance the actions of serotonin by blocking serotonin reuptake at the neuronal membrane.

Pharmacokinetics/pharmacodynamics

Fluoxetine is well absorbed from the GI tract, although food can delay the rate but not the extent of absorption. It is metabolized in the liver to an active metabolite, and both forms

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Howe-Headaches Page 23 reach steady-state plasma concentrations in 2-4 weeks. Peak plasma concentrations are reached in 6-8 hours, and elimination is quite slow with a half-life of 4-6 days for fluoxetine and 16 days for its active metabolite, norfluoxetine. Approximately 60% of an oral dose is excreted in urine within 35 days and roughly 28% excreted in feces within 28 days.

Dosages and formulations

Fluoxetine is available as 10 mg, 20 mg and 40 mg caps, 90 mg (weekly) delayed-release caps and 20 mg/5mL oral solution. In clinical trials, initial doses of 20 mg fluoxetine were increased to 40 mg depending on the patient’s response.22

Contraindications

Fluoxetine should not be used in patients receiving MAOI therapy. Patients with fluoxetine hypersensitivity should not use fluoxetine and it should be used with caution in patients with seizure disorder, liver disease, severe renal impairment or kidney failure, diabetes, and anorexia nervosa. Pregnant women should discuss their use of antidepressants with their doctors. Fluoxetine should be used with caution in breastfeeding women.

Complicating factors and adverse effects

SSRIs should not be discontinued abruptly and should not be used in children younger than 7 years. Antidepressants can induce suicidality in pediatric patients. Other adverse effects may include impaired thinking and judgment, reduced bone density, and glaucoma.

Valproic Acid, Divalproex sodium (Depakote® Delayed Release Tablets, Depakote® ER,

Stavzor™)23

Divalproex sodium is an anticonvulsant that has been shown to decrease migraine

frequency and severity. Since Divalproex sodium is rapidly converted to valproic acid in the body, the two drugs show similar properties. Depakote ER, a once daily formulation, was

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Howe-Headaches Page 24 approved by the FDA for migraine prophylaxis in August 2000. In July 2008, a delayed-release valproic acid capsule formation (Stavzor) was approved by the FDA for migraine prophylaxis.23

Mechanism of action

The exact mechanism of action for valproic acid is unknown although it is believed to increase brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory

neurotransmitter. Valproic acid may inhibit the catabolism of GABA or block its reuptake into nerve endings. It may also work by inhibiting voltage-sensitive sodium channels, thereby inhibiting repetitive neuronal firing.

Pharmacokinetics/pharmacodynamics

In terms of plasma concentrations, patient responses to a given dose vary widely. Valproic acid is approximately 90% protein-bound, but protein binding decreases as the

concentration of the drug increases which may affect its clearance from the body. Valproic acid is metabolized in the liver to more than ten metabolites, and at least one of the metabolites acts in a similar way to the original compound. Its half-life is 6-16 hours in adults, and it is eliminated through the kidneys with very little as unchanged drug. Following oral administration, its bioavailability is almost 100%. Food can delay the rate but not the extent of absorption. Depakote ER is not bioequivalent to Depakote delayed release tablets even at the same daily dosage. After multiple doses, Depakote ER given daily produces fluctuations in concentration up to 20% lower than Depakote delayed release given 2, 3, or 4 times daily. Peak plasma concentrations are reached within 3-5 hours for Depakote delayed release tablets and within 4-17 hours for Depakote ER. In either case, full therapeutic effects require several days of treatment.

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Howe-Headaches Page 25 Depakote is available in 125 mg, 250 mg and 500 mg tablets of divalproex sodium delayed release formula. The recommended initial dose of Depakote for migraine prophylaxis in adults and adolescents older than 16 is 250 mg taken twice daily. The dose can be titrated upwards as needed to 500 mg twice daily. Elderly patients should be started at a reduced initial dose with a slower dose titration. In patients with decreased food or fluid intake, or experiencing excessive drowsiness, the dose should be reduced or eliminated.

Depakote ER is available as 250 mg and 500 mg of valproic acid equivalent in extended release tablets. The recommended initial dose of Depakote ER in adults and adolescents older than 16 is 500 mg once daily for 1 week. It can then be increased to 1000 mg once daily, which should be the maximum dose. Dose adjustment may be necessary depending on tolerability and response, especially in patients with decreased food or fluid intake or excessive somnolence. If a patient requires smaller dose adjustments than are allowed with Depakote ER, Depakote should be used instead.

Stavzor is available as 125 mg, 250 mg and 500 mg of valproic acid in delayed-release capsules. The initial dose for adults is 250 mg twice daily which can be titrated as needed up to a maximum of 500 mg twice daily. In the elderly, a reduced initial dose and slower dose titration may be necessary. As with other formulations, dose adjustment may be necessary depending on tolerability and response, especially in patients with decreased food or fluid intake or excessive somnolence.

Contraindications

Patients with liver disease or urea cycle disorders should not be given valproic acid. It should be used with caution in patients with renal disease, and patients with known hypersensitivity to the drug should not use Depakote or Stavzor.

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Howe-Headaches Page 26 Complicating factors and adverse effects

Adverse effects include liver failure, pancreatitis, suicidal behavior, thrombocytopenia, hyperammonemia, hypothermia, multi-organ hypersensitivity reactions, and extreme drowsiness in the elderly. Valproic acid is distributed in spinal fluid, saliva, and milk, and crosses the blood-brain barrier. It should not be used during pregnancy.

Gabapentin (Neurontin)24

Overview

Gabapentin is an analgesic that also tends to prevent seizures, although the mechanism by which it does either is unknown. Gabapentin produces few side effects including dizziness, somnolence, weight gain, nausea, and peripheral edema.

Mechanism of action

Gabapentin appears to have an effect on voltage-dependent calcium ion channels that interrupts the events leading to the experience of a neuropathic pain sensation.

Pharmacokinetics/pharmacodynamics

Gabapentin is not metabolized in the body and is excreted in the urine as an unchanged drug. Its bioavailability is not dose proportional─as the dose increases, its bioavailability decreases. Food has very little effect on the rate and extent of absorption of gabapentin. It has an elimination half-life of 5-7 hours.

Formulations and dosages

Neurontin is available in hard capsule form at 100 mg, 200 mg, and 400 mg doses; in film-coated tablets containing 600 mg and 800 mg of gabapentin; and as an oral solution containing 250 mg/5 mL of gabapentin. The dose of gabapentin recommended for use in treating chronic migraine is 900-2700 mg with a maximum dose of 1200 mg per dose.

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Howe-Headaches Page 27 Contraindications

Neurontin is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients.

Adverse effects and complicating factors

Patients taking antiepileptic drugs, including Neurontin, may experience an increase in suicidal thoughts and behavior and should be monitored for depression and related changes in mood or behavior. Gabapentin is secreted in breast milk.

Topiramate (Topamax®)25

Topiramate is an antiepileptic drug that acts by blocking the spread of seizures rather than by raising the seizure threshold. In August 2004, topiramate was approved by the FDA for the prophylactic treatment of migraines in adults.

Mechanism of action

The exact mechanism of action of topiramate in migraine prophylaxis is not known, but its actions are of several types, any of which or all may contribute to its ability to prevent migraines. Topiramate blocks voltage-sensitive sodium channels, enhances GABA activity at GABA-A receptors, and inhibits excitatory transmissions.

Pharmacokinetics/pharmacodynamics

Topiramate is metabolized minimally and is 15-41% bound to protein. Six metabolites have been identified, none of which constitutes more than 5% of an administered dose.

Approximately 70% of an administered dose is eliminated in urine as unchanged drug. Its mean plasma half-life is 21 hours after single or multiple doses, and steady-state

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Howe-Headaches Page 28 concentration is reached in about 2 hours after a 400 mg dose, and its bioavailability is approximately 80% from tablets. Food does not affect its bioavailability. Topiramate clearance may be reduced in patients with renal or hepatic impairment.

Dosages and formulations

Topamax is available in tablets with 25 mg, 50 mg, 100 mg, and 200 mg doses of

topiramate and in “sprinkle capsules” at 15 mg, 25 mg doses. In adults, the dose is titrated upward over a period of four weeks. The initial dose is 25 mg once per day in the evening, followed by slow titration at 25 mg per week to a target of 100 mg twice a day (morning and evening) adjusted according to clinical outcome.

Contraindications

Patients with known hypersensitivity to the drug or its components should not take topiramate. If discontinued, topiramate should be withdrawn gradually. It should be used with caution in patients with a history of kidney stones, renal impairment, and liver disease, and with extreme caution in pregnant and breastfeeding women.

Complicating factors and adverse effects

Common adverse effects of topiramate include extreme drowsiness, dizziness, difficulty with concentration, and other cognitive and neuropsychiatric events. Patients with eye diseases who are taking topiramate should be monitored closely for visual disturbances. Patients taking topiramate may be more susceptible to heat stroke and other heat-related disorders.

Botulinum Toxin Type A

Botulinum toxin type A (Botox® [Btt A] was approved by the FDA in 1989 for the treatment

of several eye conditions. It gradually earned acceptance as a treatment to reduce forehead wrinkles and was approved for that indication by the FDA in 2002. Quite by accident, it was

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Howe-Headaches Page 29 observed that the injections into the skin of the forehead prevented migraine headaches. Since then, several controlled trials have confirmed this discovery and the FDA approved Botox for chronic migraines in October 2010. A Botox treatment for migraine, which includes 31 injections at seven sites around the head and neck, takes 5-10 minutes and is minimally uncomfortable. Side effects from the injections are minimal and the prophylactic effect lasts an average of 3 months. 26

Conclusion

The accurate diagnosis and treatment of headache remains difficult and is complicated by the range of medication types available. The near universality of headache as a malady is reason to hope for more research into specific causes and specialized new treatments.

Works Cited

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15. “Amitriptyline.” Migraines.org Web Site. n.d. Web. 24 Feb 2012.

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Migraine.” Semin Neurol. 2010;30(2):154-166. Medscape. Web. 29 Feb 2012.

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24. Neurontin. [prescribing information]. Pfizer Web site. Web. 29 Feb. 2012. PDF file. 25. “Topiramate, Topamax.” Gold Standard Inc. 25 Oct 2011. MDConsult. Web. 29 Feb 2012. 26. Dodick DW. “OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the

double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program.” [abstract] Headache. 01-JUN-2010; 50(6): 921-36. PMID: 20487038. MDConsult. Web. 29 Feb 2012.

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