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
CASE 58-2, QUESTION 3: V.M. has been counseled previously regarding the cardiovascular risks
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.
with a diagnosis of migraine with aura, a twofold increase in ischemic stroke risk has
136 An additional finding in this meta-analysis supported an increased
risk among migraine patients using oral contraceptives.
Organization considers migraine with aura in women of any age an absolute
contraindication to the use of combined oral contraceptives.
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.
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
Given the severity of symptoms and past treatment experience with conventional
analgesics, the selection of a migraine-targeted treatment (e.g., ergot alkaloid,
zolmitriptan are available as nonoral formulations, and either
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
CASE 58-2, QUESTION 5: V.M. has now returned to her PCP reporting success in managing her migraines
propranolol. Which medication may be prescribed to prevent migraines in V.M.?
Amitriptyline is an appropriate first-line therapy option for migraine
137 with such effects being independent of antidepressant activity.
Demonstrated blockade of sodium currents in trigeminal neurons and blockade of 5-
is the basis for the potential efficacy in managing migraine,
a complete mechanism has not been fully elucidated. Amitriptyline treatment has been
associated with significant improvement in MIDAS scores
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
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
143 Two separate studies have provided comparison between amitriptyline
145 With a primary efficacy measure of monthly migraine episode
rate, 100-mg doses of each proved comparable and similarly well tolerated.
smaller study reported similar results; however, the combination treatment of
amitriptyline and topiramate was assessed as a separate, third treatment arm.
Patient satisfaction among subjects taking the combination was noted to be higher
relative to either monotherapy group.
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
While generally tolerated, common adverse effects attributed to amitriptyline
treatment have included drowsiness, anticholinergic effects, and weight
Topiramate is considered a first-line option for migraine prophylaxis.
addition to aforementioned comparisons with amitriptyline, prospective studies have
reported similar efficacy between topiramate and sodium valproate.
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,
150 have been assessed. Evidence
supports dose titration to 100 mg for optimal outcomes.
mg has not demonstrated significantly better outcomes relative to 100 mg.
Paresthesia, fatigue, weight loss, memory, and concentration deficits have been
associated with topiramate therapy.
Valproate and divalproex sodium are approved for migraine prophylaxis and are
viable treatment options for prevention.
137 An extended-release divalproex sodium
formulation has demonstrated efficacy relative to placebo.
comparators, equivalence in efficacy has been reported for propranolol
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
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,
147 Potential for hepatotoxicity and pancreatitis
Gabapentin possesses a complex mechanism of modulating Ca
GABA concentration centrally, and binding to gabapentin-binding protein.
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.
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.
migraine frequency (number of days) and duration (number of hours) were favorable
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.
As both cortical spreading depression and gap junctional modulation have been
the inhibition of CSD constitutes a potential approach
161 Tonabersat functions as a gap junction blocker.
163 with efficacy exclusive to migraine with
160 Tonabersat is currently an investigational treatment.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
Effectiveness as preventive therapy is considered to be modest compared with the
121 NSAIDs may be effective as short-term therapy for menstruationassociated migraine.
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
frequency of both her “throbbing” and “dull,
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)
migraine and tension-type headache sufferers.
164 The pathophysiology of medication
overuse headache is multidimensional and is related to hypometabolism in
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.
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.
design of medication withdrawal procedures can be tapered or abrupt, with a tapered
withdrawal procedure recommended for opioid, barbiturate, or benzodiazepine
168 Abrupt discontinuation can be considered suitable for triptans and
168 For L.D., the discussion of a discontinuation strategy would
be recommended. Such an intervention has demonstrated positive outcomes in
170 Further, prophylaxis may be considered and topiramate has
demonstrated efficacy in this context.
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.
more common among males with an average age of onset around 30 years.
Cluster headache is characterized by severe, unilateral pain, potentially described
as a pulsating or burning sensation, often involving the orbital, temporal, or maxilla
In addition to pain, cluster headache typically involves autonomic
features (e.g., miosis, nasal congestion, ptosis, lacrimation).
The pathology surrounding cluster headache includes stimulation of parasympathetic
outflow, disturbance at the level of the hypothalamus, and vasodilation.
pathology is also a function of alterations in testosterone levels,
diminished response to thyrotropin-releasing hormone.
pineal functioning in the context of cluster headache have revealed anomalies in
serial plasma melatonin sampling, reflected as diminished peaks.
further includes angiographic changes and the interplay of parasympathetic and
sympathetic function at the level of the cavernous sinus.
rhinorrhea. He denies any premonition of ensuing headache or GI upset during the attacks. Physical
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
An aura may precede a cluster headache episode; however, this effect occurs in a
179 The episodic timeline of cluster headache is
variable, extending from weeks to months, with the potential for extended remission
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?
The treatments of choice for abortive treatment of cluster headaches are sumatriptan
by subcutaneous injection, zolmitriptan nasal spray, and oxygen inhalation.
Among these agents, subcutaneous sumatriptan is often preferred.
Sumatriptan 6 mg administered subcutaneously for cluster headaches reduced
severity in 74% of attacks within 15 minutes,
compared with 26% of attacks treated with placebo.
182 An additional injection of 6
mg does not appear to give additional headache relief.
experience a recurrent headache after initial relief with sumatriptan, a second
176 Sumatriptan should not be used more often than twice
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.
Oxygen may be useful for patients with frequent cluster headaches who would
otherwise exceed maximal dosing restrictions of sumatriptan.
oxygen’s effect is unknown but may be related to a direct vasoconstrictive action.
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.
imparted no significant beneficial effect relative to placebo.
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.
OTHER THERAPEUTIC INTERVENTIONS
The somatostatin analog, octreotide, administered by subcutaneous injection, has
demonstrated superiority in efficacy relative to placebo.
relief at 30 minutes, octreotide administration yielded improved outcomes for
resolving associated cluster headache symptoms.
interventions include intranasal capsaicin,
local administration of cocaine, and the
local administration of lidocaine.
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.
cluster period? Which option is most appropriate for R.H.?
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.
Evidence supports verapamil efficacy in cluster headache prophylaxis
with daily doses in the range of 240 to 320 mg.
electrocardiography should be performed for those maintained on verapamil
175 The need for such monitoring is a function of verapamil’s
electrophysiologic effects on cardiac nodal tissue.
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.
Lithium serum levels associated with efficacy in cluster headache prophylaxis are
usually between 0.4 and 0.8 mEq/L.
In addition to assessing serum levels, routine
monitoring of electrolytes, hepatic, renal, and thyroid function is required.
SUBOCCIPITAL STEROID INJECTION
One high-quality randomized, controlled trial demonstrated the efficacy of
suboccipital steroid injection for the prophylaxis of cluster headache in 26
Injections included 12.46 mg of betamethasone dipropionate and 5.26 mg
(compared with none in the placebo group).
Topiramate has demonstrated efficacy for cluster headache prophylaxis.
study of patients with prior prophylactic treatment exposure, topiramate produced
favorable outcomes, inducing remission in greater than 50% of treated patients.
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
Prevalence of tension-type headache is variable but has been shown to be as high as
203 Women are slightly more affected by tension-type headaches than men,
204 Tension-type headache is typically bilateral and is
characterized by a milder pain intensity and a tightening quality.
vomiting are not typical of tension headache presentation but photo- or phonophobia
Headache frequency is an important determinant for tension headache
classification, expressed in terms of headache days/month.
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
The pathology of tension headache is theorized to be a function of both peripheral
205 Modulation of trigeminal nociceptors and pericranial
muscle strain fit within this pathology.
General Management and Abortive Therapy
complaint of recurring headaches
normal. What measures should be taken to relieve K.B.’s headaches? What is an appropriate goal for
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.
Conventional analgesics, including NSAIDs, are appropriate first-line treatments for
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.
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
agents are available for continuous suppression of K.B.’s tension-type headaches?
Prophylaxis is relevant in the context of both frequent, episodic tension headache and
202 Amitriptyline has demonstrated efficacy in managing
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
209 Superiority for mirtazapine was demonstrated in measures of headache
frequency, intensity, and duration for patients with prior treatment experience.
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
Practices in the areas of spiritual meditation,
210 cognitive therapy and stress
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.
usage was similarly reflected in this cohort; however, neither pain sensitivity or
Interventions directed toward stress reduction, while deemed
feasible, have not met statistical significance for changes in headache severity or
211 Although stress reduction favorably impacted MIDAS and HIT-6
assessments relative to controls, the study lacked the statistical power to confer
211 Similarly, traditional acupuncture has yielded headache-associated
pain relief; however, prospective trials are warranted to better elucidate the
therapeutic impact of this practice.
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