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CASE 58-2, QUESTION 2: Should the migraine that V.M. is experiencing be treated according to a

stratified-care or step-care model?

In accordance with a step-care model, a conventional analgesic medication would

be considered as primary therapy.

61 A stratified-care approach is designed for

treatment selection based on patient need.

61 V.M. has reported self-treatment with

conventional agents (e.g., naproxen or ibuprofen) without adequate relief. Further

considering that V.M.’s MIDAS score corresponds to “moderate” disability and the

reported variance of MIDAS score with age,

34 a stratified-care model would be

preferable.

CASE 58-2, QUESTION 3: V.M. has been counseled previously regarding the cardiovascular risks

associated with oral contraceptives and questions whether she is at greater risk considering her migraine

diagnosis. Is an oral contraceptive appropriate for V.M.?

No consistent increased risk for stroke has been found among men, women older

than 45 years old, and women who have migraine without aura.

135 Among patients

with a diagnosis of migraine with aura, a twofold increase in ischemic stroke risk has

been reported.

136 An additional finding in this meta-analysis supported an increased

risk among migraine patients using oral contraceptives.

136 The World Health

Organization considers migraine with aura in women of any age an absolute

contraindication to the use of combined oral contraceptives.

51 The American College

of Obstetricians and Gynecologists guidelines permit the use of combined oral

contraceptives in women who suffer from migraine with aura as long as they have no

focal neurologic signs, do not smoke, and are younger than 35 years of age.

51 V.M.

describes herself as an “occasional smoker” so relevant management strategies

include discussing other contraceptive options and/or a smoking cessation plan.

CASE 58-2, QUESTION 4: What is the most appropriate recommendation for acute management of V.M.’s

migraine?

Given the severity of symptoms and past treatment experience with conventional

analgesics, the selection of a migraine-targeted treatment (e.g., ergot alkaloid,

triptan) would be preferable. Of similar importance is the presence of severe, earlyonset nausea; therefore, a nonoral administration is recommended. Sumatriptan and

zolmitriptan are available as nonoral formulations, and either

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p. 1242

could be considered appropriate for V.M. A limiting factor in the selection of

ergot alkaloids as a primary treatment would be the potential for drug-associated

nausea.

107

CASE 58-2, QUESTION 5: V.M. has now returned to her PCP reporting success in managing her migraines

with zolmitriptan. The frequency of migraine episodes remains an issue, reporting 4–5 episodes monthly which

have caused her to miss work. Her PCP is considering prophylactic treatment but would prefer not to prescribe

propranolol. Which medication may be prescribed to prevent migraines in V.M.?

AMITRIPTYLINE

Amitriptyline is an appropriate first-line therapy option for migraine

prophylaxis

121

,

137 with such effects being independent of antidepressant activity.

138–140

Demonstrated blockade of sodium currents in trigeminal neurons and blockade of 5-

HT reuptake

141

is the basis for the potential efficacy in managing migraine,

140 although

a complete mechanism has not been fully elucidated. Amitriptyline treatment has been

associated with significant improvement in MIDAS scores

142 Such an effect has been

demonstrated following a 45-day treatment cycle.

142 Particularly applicable to the

case of V.M., there is demonstrated benefit for amitriptyline in the treatment of

tension-type headache as well,

9 making it a viable option for patients with both

headache forms.

Amitriptyline has been compared with propranolol, divalproate, and topiramate in

various studies. A randomized trial comparing extended-release divalproate with

amitriptyline (150 subjects in each treatment group) yielded similar efficacy,

measured by headache frequency at 6 months, while being inferior to divalproate at 3

months.

143 Two separate studies have provided comparison between amitriptyline

and topiramate.

144

,

145 With a primary efficacy measure of monthly migraine episode

rate, 100-mg doses of each proved comparable and similarly well tolerated.

144 A

smaller study reported similar results; however, the combination treatment of

amitriptyline and topiramate was assessed as a separate, third treatment arm.

145

Patient satisfaction among subjects taking the combination was noted to be higher

relative to either monotherapy group.

145

Dosing

The initial dose of amitriptyline is 10 to 25 mg by mouth at bedtime. This nightly

dose can be increased at weekly intervals by 10 to 25 mg until the maximal dose of

150 mg/day is reached.

While generally tolerated, common adverse effects attributed to amitriptyline

treatment have included drowsiness, anticholinergic effects, and weight

increase.

143–145

TOPIRAMATE

Topiramate is considered a first-line option for migraine prophylaxis.

121

,

137

In

addition to aforementioned comparisons with amitriptyline, prospective studies have

reported similar efficacy between topiramate and sodium valproate.

146–148 Three large

randomized, placebo-controlled trials have documented the efficacy of this agent for

reducing the number of monthly attacks.

149 With initial dosing of 25 mg daily,

144

,

145

,

150

target doses of 100 mg daily

144 and 200 mg daily

150 have been assessed. Evidence

supports dose titration to 100 mg for optimal outcomes.

148

,

151 Further titration to 200

mg has not demonstrated significantly better outcomes relative to 100 mg.

148

,

152

Paresthesia, fatigue, weight loss, memory, and concentration deficits have been

associated with topiramate therapy.

144

,

145

,

153

VALPROATE

Valproate and divalproex sodium are approved for migraine prophylaxis and are

viable treatment options for prevention.

121

,

137 An extended-release divalproex sodium

formulation has demonstrated efficacy relative to placebo.

154 Versus active

comparators, equivalence in efficacy has been reported for propranolol

155 and

topiramate.

147 The selection of valproate as a therapy for women of childbearing age

must be evaluated cautiously, in light of potential detrimental effects in cognitive

development.

156

Dosing

Delayed- or extended-release formulations of divalproex sodium (e.g., Depakote or

Depakote ER) may be prescribed for prophylaxis with the advantage of the latter

formulation being once-daily administration. Initial dosing for the delayed-release

formulation is 250 mg by mouth twice daily whereas the extended-release

formulation is 500 mg by mouth once daily.

Adverse effects associated with valproate treatment include alopecia, nausea,

drowsiness, and weight gain.

147 Potential for hepatotoxicity and pancreatitis

157

limits

utility.

GABAPENTIN

Gabapentin possesses a complex mechanism of modulating Ca

++ channels, increasing

GABA concentration centrally, and binding to gabapentin-binding protein.

158 A

randomized trial versus placebo demonstrated superiority of gabapentin 2,400

mg/day in reducing migraine rate over 4 weeks.

158 Secondary outcomes related to

severity, functional capacity, duration, and aura severity did not yield significant

differences between treatment groups.

158

CANDESARTAN

Candesartan, an angiotensin II type 1 (AT1

) receptor antagonist, has demonstrated

efficacy, based on an intention-to-treat analysis of 57 patients, in migraine

prophylaxis in a randomized, placebo-controlled, crossover design.

159 Outcomes of

migraine frequency (number of days) and duration (number of hours) were favorable

with candesartan.

159 Although dizziness was the most frequently reported adverse

event associated with treatment, neither this effect nor any other adverse outcome

differed significantly from placebo.

159

TONABERSAT

As both cortical spreading depression and gap junctional modulation have been

linked with migraine aura,

20

,

131

the inhibition of CSD constitutes a potential approach

to treatment.

160

,

161 Tonabersat functions as a gap junction blocker.

161 Comparisons

with placebo have been mixed

160

,

162

,

163 with efficacy exclusive to migraine with

aura.

160 Tonabersat is currently an investigational treatment.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Effectiveness as preventive therapy is considered to be modest compared with the

first-line agents.

121 NSAIDs may be effective as short-term therapy for menstruationassociated migraine.

121

In selecting an alternative prophylactic medication for V.M., evidence supports

use of either a selective β-antagonist (e.g., metoprolol), amitriptyline, or topiramate.

In all such instances, V.M. should be counseled with regard to dose titrations,

adverse effects, and allowing for a sufficient trial duration to adequately determine

efficacy.

Medication Overuse

CASE 58-3

QUESTION 1: L.D. is a 39-year-old woman with a 7-year history of migraine (without aura) and tension-type

headache who comes to the clinic requesting a refill of her almotriptan. She reports an increase in the

frequency of both her “throbbing” and “dull,

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p. 1243

pressure sensation” headaches during the past year, and lately she has had difficulty distinguishing the two

types. In the past 2 months, she has had only 5 days with no headache, and she has been much less productive

in her work as a magazine editor. She has reported using 4 to 5 almotriptan tablets weekly with multiple

episodes also requiring naproxen sodium, which she has purchased over the counter (OTC). She has requested

two refills for her almotriptan during the past 1½ months. What is the role of medication overuse in worsening

symptoms, and how should this condition be managed in L.D.?

Medication overuse is defined as the use of triptans, ergot alkaloids, opioid

analgesics, or combination analgesics on 10 or more days/month (the criterion for

use of simple OTC analgesics is 15 or more days/month)

137 and often occurs in

migraine and tension-type headache sufferers.

164 The pathophysiology of medication

overuse headache is multidimensional and is related to hypometabolism in

neuroanatomic structures,

164

,

165 neurochemical alterations (e.g., orexinA,

corticotropin-releasing factor),

166 and alterations in receptor expression and

neuropeptide levels (e.g., increase in CGRP).

167 Chronic daily headaches often have

features of both migraine and tension-type headaches.

168 L.D. displays many of the

features of medication overuse headache. She reports an increase in the frequency of

headaches to a near-daily pattern, and she is no longer able to distinguish between

migrainous and tension-type headaches. Laboratory tests should be ordered to assess

L.D.’s renal and hepatic function, and she should be questioned regarding the

occurrence of GI discomfort, acute bleeding, or a change in her stool color.

In general, patients who receive abortive agents for headache treatment should be

counseled to restrict their use of these agents to no more than twice/week.

121 The

design of medication withdrawal procedures can be tapered or abrupt, with a tapered

withdrawal procedure recommended for opioid, barbiturate, or benzodiazepine

overuse.

168 Abrupt discontinuation can be considered suitable for triptans and

nonopioid analgesics.

168 For L.D., the discussion of a discontinuation strategy would

be recommended. Such an intervention has demonstrated positive outcomes in

headache reduction.

169

,

170 Further, prophylaxis may be considered and topiramate has

demonstrated efficacy in this context.

168

,

171

CLUSTER HEADACHE

Cluster headache is an uncommon headache disorder (estimated prevalence 0.07%–

0.4%) that derives its name from the characteristic pattern of headache recurrence—

headaches tend to occur nightly during a relatively short time (e.g., several weeks or

months), followed by a long period of complete remission.

172 Cluster headache is

more common among males with an average age of onset around 30 years.

173

Cluster headache is characterized by severe, unilateral pain, potentially described

as a pulsating or burning sensation, often involving the orbital, temporal, or maxilla

regions.

5

,

174

In addition to pain, cluster headache typically involves autonomic

features (e.g., miosis, nasal congestion, ptosis, lacrimation).

5

,

174

Pathophysiology

The pathology surrounding cluster headache includes stimulation of parasympathetic

outflow, disturbance at the level of the hypothalamus, and vasodilation.

175

,

176 Such

pathology is also a function of alterations in testosterone levels,

175 melatonin,

175 and

diminished response to thyrotropin-releasing hormone.

175 Further assessments of

pineal functioning in the context of cluster headache have revealed anomalies in

serial plasma melatonin sampling, reflected as diminished peaks.

177 The pathology

further includes angiographic changes and the interplay of parasympathetic and

sympathetic function at the level of the cavernous sinus.

178

Signs and Symptoms

CASE 58-4

QUESTION 1: R.H. is a 31-year-old man with a 3-year history of episodic cluster headache. He has been

headache-free for the past year, but today states that the headaches are returning in their characteristic fashion.

He reports abrupt onset of right-sided retro-orbital pain with occasional superimposed knifelike “jabs” that

increase in intensity for several minutes to a severe, unrelenting pain lasting about 90 minutes. The headache

then gradually subsides. Associated symptoms include right-sided lacrimation, conjunctival injection, and

rhinorrhea. He denies any premonition of ensuing headache or GI upset during the attacks. Physical

examination during a cluster headache shows right eyelid droop and pupillary miosis. R.H.’s cluster periods

characteristically last about 2 months and usually recur once or twice yearly. The first headache of the current

episode awoke him from a short nap. R.H. expects to suffer one or two such headaches daily because this has

been the usual pattern during each cluster period. Previous cluster headaches have been symptomatically

treated with aspirin and codeine 30 mg. However, R.H. reports only modest relief with this treatment approach.

R.H.’s medical history is unremarkable. He does not use tobacco but admits to occasional social drinking.

What subjective and objective evidence in this case is consistent with a diagnosis of cluster headaches?

R.H.’s sex, age of onset, quality and intensity of headache pain, periodicity of

headache attacks, and associated symptoms all support the diagnosis of cluster

headaches.

An aura may precede a cluster headache episode; however, this effect occurs in a

small percentage of patients.

174

,

179 The episodic timeline of cluster headache is

variable, extending from weeks to months, with the potential for extended remission

periods.

5 R.H.’s headache quality (severe, unrelenting pain), site (unilateral),

evolution and resolution pattern (worsens over several minutes and resolves within

90 minutes), and periodicity of attacks (one or two headaches occurring daily for

about 2 months followed by a period of remission that lasts about 1 year) are all

compatible with the usual character of cluster headaches.

Associated symptoms reported by R.H. during headache attacks (e.g., lacrimation,

rhinorrhea, conjunctival injection) and the absence of GI or neurologic disturbances

are also compatible with the diagnosis of cluster headaches.

CASE 58-4, QUESTION 2: What abortive measures are available for symptomatic treatment of individual

headaches during R.H.’s current cluster period?

Abortive Therapy

The treatments of choice for abortive treatment of cluster headaches are sumatriptan

by subcutaneous injection, zolmitriptan nasal spray, and oxygen inhalation.

180

,

181

Among these agents, subcutaneous sumatriptan is often preferred.

182

SUMATRIPTAN

Sumatriptan 6 mg administered subcutaneously for cluster headaches reduced

severity in 74% of attacks within 15 minutes,

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p. 1244

compared with 26% of attacks treated with placebo.

182 An additional injection of 6

mg does not appear to give additional headache relief.

182 However, in patients who

experience a recurrent headache after initial relief with sumatriptan, a second

injection is often useful.

176 Sumatriptan should not be used more often than twice

daily during cluster bouts.

A randomized, multicenter trial, assessing intranasal sumatriptan (20 mg)

compared with placebo, yielded a significantly better outcome of decreased pain

response, 30 minutes following administration.

183 Secondary outcome measures,

including resolution of associated symptoms, similarly favored sumatriptan.

183

OXYGEN

Oxygen may be useful for patients with frequent cluster headaches who would

otherwise exceed maximal dosing restrictions of sumatriptan.

172 The mechanism of

oxygen’s effect is unknown but may be related to a direct vasoconstrictive action.

172

Clinical trial data have been mixed. In a trial of 57 patients with episodic cluster

headache, 100% oxygen delivered at 12 L/minute was deemed more effective versus

placebo for achieving pain-free status at 15 minutes.

184 A double-blind, placebocontrolled cross-over study of hyperbaric oxygen treatment for cluster episodes

imparted no significant beneficial effect relative to placebo.

185

ZOLMITRIPTAN

Two controlled trials have established the effectiveness of intranasal zolmitriptan for

the acute treatment of cluster headache attacks. Cluster headache relief rates were

40% and 50% with 5 mg of zolmitriptan, and 62% and 63% with 10 mg of intranasal

zolmitriptan in these two studies, respectively.

181

,

186

OTHER THERAPEUTIC INTERVENTIONS

The somatostatin analog, octreotide, administered by subcutaneous injection, has

demonstrated superiority in efficacy relative to placebo.

187

In addition to headache

relief at 30 minutes, octreotide administration yielded improved outcomes for

resolving associated cluster headache symptoms.

187 Alternate therapeutic

interventions include intranasal capsaicin,

188

local administration of cocaine, and the

local administration of lidocaine.

189

Reasonable options for the acute treatment of R.H.’s acute cluster headaches

include subcutaneous sumatriptan, oxygen inhalation, and intranasal zolmitriptan. For

many patients, oxygen is a less convenient therapy because the equipment is not

easily portable and the patient must sit still during the treatment. The choice can be

made on the basis of patient preference or cost.

CASE 58-4, QUESTION 3: What therapeutic agents are available for headache prophylaxis during an active

cluster period? Which option is most appropriate for R.H.?

Prophylactic Therapy

Prophylaxis should be considered in the context of chronic cluster headache

episodes. An important objective for prophylactic treatment is reducing the risk of

overmedication associated with acute treatment.

175

VERAPAMIL

Evidence supports verapamil efficacy in cluster headache prophylaxis

174

,

175

,

190–192

with daily doses in the range of 240 to 320 mg.

175

,

193

,

194 Baseline and periodic

electrocardiography should be performed for those maintained on verapamil

therapy.

174

,

175 The need for such monitoring is a function of verapamil’s

electrophysiologic effects on cardiac nodal tissue.

LITHIUM CARBONATE

Where primary treatment is either ineffective or contraindicated, the use of lithium as

a second-line option is supported.

191 A double-blind, crossover study found similar

efficacy relative to verapamil yet, lithium was inferior to verapamil in tolerability.

195

Lithium serum levels associated with efficacy in cluster headache prophylaxis are

usually between 0.4 and 0.8 mEq/L.

182

In addition to assessing serum levels, routine

monitoring of electrolytes, hepatic, renal, and thyroid function is required.

191

SUBOCCIPITAL STEROID INJECTION

One high-quality randomized, controlled trial demonstrated the efficacy of

suboccipital steroid injection for the prophylaxis of cluster headache in 26

patients.

196

Injections included 12.46 mg of betamethasone dipropionate and 5.26 mg

of betamethasone disodium phosphate mixed with 0.5 mL of 2% lidocaine. Eightyfive percent of patients had relief of headache attacks within 72 hours of injection

(compared with none in the placebo group).

TOPIRAMATE

Topiramate has demonstrated efficacy for cluster headache prophylaxis.

191

,

197–201

In a

study of patients with prior prophylactic treatment exposure, topiramate produced

favorable outcomes, inducing remission in greater than 50% of treated patients.

197

Prompt consideration should be given to the aforementioned additional treatments

if suppression of headaches during the cluster period is warranted. In general, after

response to prophylactic agents such as verapamil and lithium has been established

and maintained for at least 2 weeks, attempts can be made to discontinue the drug.

Treatment should be reinstituted if headaches recur. With considerations toward

patient ease of use and efficacy, treating R.H. with verapamil or topiramate would be

rational.

TENSION-TYPE HEADACHE

Prevalence of tension-type headache is variable but has been shown to be as high as

78%.

5

,

202

,

203 Women are slightly more affected by tension-type headaches than men,

with a ratio of 5:4.

204 Tension-type headache is typically bilateral and is

characterized by a milder pain intensity and a tightening quality.

5 Nausea and

vomiting are not typical of tension headache presentation but photo- or phonophobia

may be present.

5

Headache frequency is an important determinant for tension headache

classification, expressed in terms of headache days/month.

5

,

202 Episodic tension

headache can be either infrequent (<1 day/month) or frequent (1–14 days/month),

whereas chronic tension headache is classified with a threshold of 15 headache

days/month.

5

,

202

Pathophysiology

The pathology of tension headache is theorized to be a function of both peripheral

and central pain pathways.

205 Modulation of trigeminal nociceptors and pericranial

muscle strain fit within this pathology.

205

General Management and Abortive Therapy

CASE 58-5

QUESTION 1: K.B., a 27-year-old female financial analyst, presents to her general practitioner with a

complaint of recurring headaches

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p. 1245

that worsened when she started her current job. Before this time, she had experienced infrequent headaches,

which she associated with periods of stress. The headaches would occur 3 to 4 times yearly, were of a

constant, dull, or “pressing” character, and were present around the entire head. Recently, headaches of similar

character have been occurring about 1 to 2 times weekly, usually toward the end of her workday. The pain

usually lasts the rest of the day but varies in intensity. Occasionally, a headache is present when she wakes up

in the morning as well. K.B. denies GI and aura symptoms associated with her headaches. She has noticed that

relaxation and alcohol ingestion seem to relieve these headaches, but aspirin and acetaminophen have been

ineffective. Her blood pressure is 120/74 mm Hg; her physical and neurologic examinations are completely

normal. What measures should be taken to relieve K.B.’s headaches? What is an appropriate goal for

treatment?

K.B. appears to be suffering from frequent episodic tension-type headaches. She

reports approximately four to eight headache episodes/month, and these headaches

have features that are stereotypical for tension-type headache. As in the treatment of

other chronic headache disorders, a cure for recurrent tension-type headache is

unlikely. K.B. should clearly understand that the goal of treatment is a reduction in

the frequency and severity of headache. Drug therapy and relaxation techniques are

the primary means by which tension-type headaches are treated.

ANALGESICS

Conventional analgesics, including NSAIDs, are appropriate first-line treatments for

tension headache.

202 A recent meta-analysis of four controlled trials supported the

effectiveness of both a combination product (acetaminophen, aspirin, and caffeine)

and acetaminophen relative to placebo in achieving pain-free status at 2 hours

postadministration for tension headache treatment.

206 Secondary endpoints included

pain-free status at 1 hour post, headache response at 2 hours, and level of impact on

daily activity, with results being consistent with the primary outcome measure.

206

An NSAID (e.g., ibuprofen or naproxen) would be an appropriate recommendation

for the treatment of K.B.’s tension-type headaches because of her previous

inadequate responses to aspirin and acetaminophen.

CASE 58-5, QUESTION 2: K.B. was prescribed ibuprofen 400 mg every 4 to 6 hours as needed for acute

relief of recurrent tension-type headaches. At her next scheduled follow-up visit, K.B. reported moderate relief

with ibuprofen but complained of GI upset with each dose, even when taken with food. What prophylactic

agents are available for continuous suppression of K.B.’s tension-type headaches?

Prophylactic Therapy

Prophylaxis is relevant in the context of both frequent, episodic tension headache and

chronic tension headache.

202 Amitriptyline has demonstrated efficacy in managing

tension headache.

202

,

207 A median daily dose of 75 mg yielded a significant

improvement in headache index relative to placebo.

207 Mirtazapine and venlafaxine

have both demonstrated efficacy in tension headache treatment relative to

placebo.

208

,

209 Superiority for mirtazapine was demonstrated in measures of headache

frequency, intensity, and duration for patients with prior treatment experience.

208

Given K.B.’s increasing frequency of tension-type headache and her intolerance to

moderate doses of ibuprofen, prophylactic treatment with amitriptyline would be

appropriate. A starting dose of amitriptyline 10 mg nightly, increasing by 10 to 25 mg

at 1-week intervals to a maintenance dose of 50 mg/day, should be prescribed, at

which time headache response can be assessed and the dose increased or decreased

as necessary. If effective, amitriptyline should be continued for 3 to 4 months before

gradually decreasing the dose until the drug is completely discontinued. Therapy

should be reinstituted if headaches return. Mirtazapine may be initiated as a secondline option for K. B., if amitriptyline is not effective.

Interprofessional Management

Practices in the areas of spiritual meditation,

210 cognitive therapy and stress

reduction,

211

,

212 and acupuncture

213 have been assessed in headache management. A

recent study, assessing outcome measures of headache frequency, severity, and

medication use, as impacted by either spiritual meditation, secular meditation

(internally and externally focused), or muscle relaxation, reported a favorable impact

on episode frequency induced by spiritual meditation.

210 A decrease in medication

usage was similarly reflected in this cohort; however, neither pain sensitivity or

severity differed.

210

Interventions directed toward stress reduction, while deemed

feasible, have not met statistical significance for changes in headache severity or

frequency.

211 Although stress reduction favorably impacted MIDAS and HIT-6

assessments relative to controls, the study lacked the statistical power to confer

significance.

211 Similarly, traditional acupuncture has yielded headache-associated

pain relief; however, prospective trials are warranted to better elucidate the

therapeutic impact of this practice.

213

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

Bendtsen L et al. EFNS guideline on the treatment of tension-type headache—report of an EFNS task force. Eur J

Neurol. 2010;17:1318–1325. (202)

Headache Classification Committee of the International Headache Society. The International Classification of

Headache Disorders: 3rd edition (beta). Cephalalgia. 2013;33(9):629–808. (5)

May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet. 2005;366:843–855. (175)

Marmura MJ, Silberstein SD. Current understanding and treatment of headache disorders. Neurology.

2011;76(Suppl 2):S31–S36. (28)

Marmura MJ et al. The acute treatment of migraine in adults: The American Headache Society evidence

assessment of migraine pharmacotherapies. Headache. 2015;55:3–20. (48)

Thorlund K et al. Comparative efficacy of triptans for the abortive treatment of migraine: a multiple treatment

comparison meta-analysis. Cephalalgia. 2014;34(4):258–267. (85)

Shamliyan TA et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med.

2013;28(9):1225–1237. (123)

Tassorelli C et al. A consensus protocol for the management of medication-overuse headache: Evaluation in a

multicentric, multinationalstudy. Cephalalgia. 2014;34(9):645–655. (169)

Key Websites

American Academy of Neurology. https://www.aan.com/.

American Headache Society. http://www.americanheadachesociety.org/.

American Headache Society (AHS) Committee for Headache Education. http://www.achenet.org/.

International Headache Society. http://www.ihs-headache.org/.

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