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Migraine, tension-type, and cluster headache are classified as primary
headache disorders. Subtle differences in symptomatology and the
presence of auxiliary symptoms assist in defining headache type.
Virtually all patients who suffer from migraine, tension-type, and cluster
headaches are candidates to receive abortive (or symptomatic)
medications during an acute attack. Prophylactic treatment may be
considered for all primary headache types and is driven by various
factors including headache frequency, the level of disability imparted by
the headache, and response to acute treatment modalities.
Triptans are the drugs of choice as migraine-specific treatments for
acute episodes. Triptans are effective in managing associated symptoms
of migraine (e.g., nausea, photo- and phonophobia). Differences within
the class are observed on the basis of pharmacokinetics.
Evidence supports the use of propranolol, amitriptyline, or topiramate as
first-line agents for migraine prophylaxis. The decision to initiate
prophylaxis takes into account headache frequency, the impact of
attacks on patient functioning, and response to acute treatments.
Medical history and adverse effect profile are relevant considerations
intensity and chronicity of all headache types. To prevent medication
overuse headache, use of these agents should be limited to fewer than
Cluster headaches are severely painful and short-duration attacks that
tend to occur nightly during susceptible periods and then enter remission
for a period of months or years. Treatments of choice for abortive
treatment must be fast-acting and include subcutaneous sumatriptan,
intranasal zolmitriptan, and oxygen inhalation.
Tension-type headaches (previously known as tension or muscle
contraction headaches) usually cause mild-to-moderate discomfort.
Conventional analgesics are often appropriate for acute management.
Some patients with tension-type headache may require prophylactic
treatment, for which amitriptyline, mirtazapine, and venlafaxine have
Previous investigations have determined that migraine prevalence approximates
2 Survey data obtained from the American Migraine Prevalence and
Prevention Study (2004) support the same percentage, as applied to meeting
International Classification of Headache Disorders-2 criteria.
care settings, migraine accounts for 0.5% of all encounters, with a majority occurring
in primary care settings whereas emergency department (ED) visits approximate
3 being further stratified within the top 10 causes for ED encounters in the U.S.
There is demonstrated variability across both gender and age, with a higher
1–3 and a higher prevalence between 30 and 39 years.
1 Such ageand gender-associated prevalence has been further substantiated in surveillance
There is inherent difficulty in evaluating and classifying headache, because this
symptom may be attributed to either a physiologic, psychological, or pathologic
process, or may be an adverse outcome associated with medications. Because the
processes contributing to headache are vast, it is imperative to conduct a
comprehensive patient assessment. Broadly categorized, headache is defined as
primary or secondary, with the latter typically being attributable to an organic cause.
Primary headache is inclusive of migraine, tension headache, and trigeminal
cephalalgias, of which cluster headache would be one category. Further, headache
associated with physical activity, exposure to exogenous stimuli, or those evolving
during the sleep cycle would be categorized as primary.
attributable to, but not limited to, traumatic injury, vascular or nonvascular cranial
pathology, tumor formation (neurofibroma), or an infectious process.
The appropriate classification ultimately speaks to the larger issue of optimal
management, via either medical procedures or the initiation of medication. Because
secondary headache is associated with a causative component, targeting that cause
becomes a principle intervention strategy.
The timeline for the evolution of migraine can often be expressed in terms of minutes.
The clinical assessment process for differentiating headache type is dependent upon
recognizing general characteristics of migraine and further distinguishing such
characteristics from other primary headache forms. An assessment of location can be
useful but should not be used as a prime differentiator between headache types
because migraine location can be unilateral or bilateral in nature. Patient assessment
should include an evaluation of both pain intensity and pain quality, because
migraines are commonly described as moderate-to-severe pulsating pain.
duration typically ranges from 4 to 72 hours and may be accompanied by auditory
(phonophobia) and light (photophobia) sensitivity, as well as nausea and vomiting.
These auxiliary symptoms are mediated via the hypothalamus and the chemoreceptor
trigger zone (CTZ), indicating diffuse neuroanatomic involvement. The
aforementioned features have demonstrated reliable predictive value in migraine
diagnosis, as defined by the POUND mnemonic (pulsating, 4–72 hour duration,
unilateral nature, nausea or vomiting, disabling effect).
7 The presence of 4 out of the
5 criteria indicates high probability of migraine.
Migraine may be preceded by a constellation of optical or sensory features,
defined as an aura. The presence or absence of an aura highlights an important
differentiator in migraine diagnosis. International Classification of Headache
Disorders criteria indicate a disparity in the number of episodes consistent with a
diagnosis of migraine without aura (minimum of five episodes) versus migraine with
aura (minimum of two episodes).
5 This criterion is not the only parameter
considered, because additional criteria pertaining to headache characteristics also
need to be met for an appropriate migraine diagnosis. Auras most often affect vision,
with either positive (visual feature) or negative (localized blindness) character.
Sensory effects can be characterized similarly as positive (pins and needles
description) or negative (loss of sensation or numbness).
beyond the visual and sensory, such as motor or speech irregularity, is linked more
toward specialized migraine diagnoses.
5 Patients with suspected migraine should be
advised to document aura timing and description, because this information can be
valuable for accurate diagnosis.
Patient report of pain location in migraine may be widespread due to the branching
of the trigeminal nerve, which facilitates sensory effects across facial regions.
Anatomically, the trigeminal nerve features branches of V1, V2, and V3.
innervates the scalp, orbital region, and meninges, V2 is directed to the top of the jaw
and sinus region, and V3 innervates lower mandibular regions.
patients may report pain referral to the suboccipital region due to the close proximity
between occipital nerves and the spinal nucleus.
Cluster headache is characterized within the domain of primary headache disorders.
Whereas migraine can be unilateral or bilateral, cluster headache is primarily
unilateral involving orbital and/or temporal pain, which can persist for up to 3
Independent of duration, such episodes may occur multiple times during the
5 Associated symptoms that occur with high prevalence during cluster headache
include lacrimation, rhinorrhea, miosis, ptosis, diaphoresis, and flushing.
Preferential incidence of cluster headache occurs in males, but there is similarity to
migraine on the basis of age prevalence.
Tension-type headache is of bilateral character and by comparison to migraine, is
often associated with less intense pain without a pulsating quality. An individual’s
subjective description of pain quality and intensity can be useful in differentiation.
Patients may use such terminology as “tightening” to characterize symptoms. The
combination of symptoms of photophobia, phonophobia, and nausea/vomiting is not
considered to be consistent with the diagnosis of tension headache; however, the
individual symptoms of photo- or phonophobia may accompany tension-type
To complete the discussion pertaining to primary headache pathology, the
International Headache Society (IHS) defines headache in association with cough,
exercise, sexual activity, cold stimuli, and external compression under the umbrella
of primary headache disorders.
Causation is the key principle underlying secondary headache. Such attributable
causes include head or neck trauma, cervical vascular dysfunction, nonvascular
cranial dysfunction, infection, psychiatric pathology, or substance withdrawal
5 Causation becomes a critically important principle to consider in patient
assessment, particularly when headache onset deviates substantially from existing
prevalence and epidemiologic data.
Acute headaches may be linked to subarachnoid hemorrhage, stroke, meningitis, or
intracranial mass (e.g., neurofibroma, abscess, etc.). It is within this clinical context
that diagnostic measures of neuroimaging and lumbar puncture are more commonly
implemented. Commonalities of headaches associated with such pathology are of
severe quality and rapid evolution, perhaps described as the “worst headache”
experienced. An increase in intracranial pressure is of particular importance, and
recognition of factors that can impact intracranial pressure becomes critical in patient
Subacute headaches may be a sign of increased intracranial pressure, intracranial
mass lesion, temporal arteritis, sinusitis, or trigeminal neuralgia. Trigeminal
neuralgia usually occurs after the age of 40 and is more common in women than in
men. The pain usually occurs along the second or third divisions of the trigeminal
(facial) nerve and lasts only moments. Trigeminal neuralgia is characterized by
sudden, intense pain that recurs paroxysmally, often in response to triggers such as
The evaluation of headache pathology should incorporate the consideration of
reported prevalence data, patient age, the presence of triggers or aggravating factors,
the contribution of past medical history to headache origin, the patient’s description
and characterization of symptoms and frequency, and any record of self-care
interventions employed to manage headache. Evaluating the impact of headache on
daily activity and function is a similarly important consideration. A diagnosis may be
confirmed on the basis of this information without the need for further laboratory or
procedural measures. If objective or subjective information becomes suggestive of a
clinical anomaly (e.g., late-age onset of headache, suspected structural anomalies or
neural tissue pathology, etc.), a more comprehensive evaluation, inclusive of
additional diagnostic measures (e.g., imaging, lumbar puncture), is indicated.
The pathologic picture of headache requires an understanding of vascular physiology
and the functions of the trigeminovascular circuit and neuropeptides. Headache
involves both peripheral and central pain processing, afferent neuronal excitability,
and pain sensitivity of cerebral arteries and venous sinuses.
often been described within the context of interactions between vascular and
10 Muscular tenderness similarly contributes to headache
11 Such an effect is more commonly considered in association with
Recent evidence has conferred support for the interplay between vascular and
neurologic function. Afferent and efferent fibers of the trigeminovascular circuitry,
vasoactive neuropeptides stored within this system, and serotonin (5-HT) maintain
significant pathologic importance.
13 Neuropeptides, such as substance P,
Recent evidence further suggests an elevation in pro-inflammatory C-reactive protein
in migraine sufferers compared to controls.
14 Consequently, therapeutic interventions
have focused on modulating the effects of 5-HT with recent efforts directed toward
the modulation of neuropeptide function.
The primary goal of therapy is the resolution of headache symptoms, most
prominently pain, and attenuating disability associated with the headache.
Nonpharmacologic recommendations should similarly be paired with therapeutic
options. Pharmacologic treatment options can be divided into abortive and
prophylactic, the former resolving acute episodes and the latter being administered
chronically to reduce the incidence of recurrent headaches. Abortive treatment may
sufficiently manage tension-type headache, often negating the need for prophylactic
treatment; however, this may be considered when acute treatment is ineffective,
overused, or when the headache is chronic or occurring in frequent episodes.
Conversely, patients with migraine and cluster headache, while requiring abortive
treatment, may commonly also require long-term prophylactic treatment.
Success in managing acute episodes can often be achieved with the use of
conventional analgesics or headache-specific medications (e.g., dihydroergotamine,
triptans). Medication selection should be based on the patient’s prior treatment
experience and the level of disability imparted by the headache episode. With regard
to prophylactic therapy, evidence supports the use of select antidepressants,
anticonvulsants, and antihypertensives. The selection of such agents should be
considered within the context of adverse effect profiles and the potential for utility in
managing other medical conditions (e.g., prescribing a β-antagonist for migraine
prophylaxis in a patient with a history of hypertension). Rational prescribing limits
both the potential for polypharmacy and the risk of adverse effects.
Migraine is characterized by pain of a throbbing quality with moderate-to-severe
intensity and the presence of associated symptoms, including nausea, vomiting, light,
6 Migraine can be unilateral or bilateral and can be
further classified on the presence of an aura.
5 The occurrence of an aura has
diagnostic relevance based upon the number of episodes and can encompass a range
of sensory disturbance, not solely limited to visual field effects.
Vascular constriction was a prior central focus of migraine pathology, resulting in
hypoperfusion and being resolved through compensatory vasodilation.
alterations in blood flow have been observed in neuroimaging of migraine
16–18 There are further alterations in neuronal depolarization, termed
cortical spreading depression.
20 There has been further demonstration of causality
between cortical spreading depression and the activation of trigeminovascular
Implications of cortical spreading depression include changes in pH,
nitric oxide concentration, and the glutamatergic system.
system consists of afferent fibers with a foundation in trigeminal ganglia, projecting
peripherally to intracranial blood vessels and venous sinuses and to extracranial
22 Trigeminal branches innervate the scalp, orbit, meninges, and mandibular
8 Activation of the trigeminovascular system facilitates the release of
24 Further effects include the activation of both the superior
salivary nucleus and parasympathetic efferent fibers.
Evidence from positron emission tomography scanning (a technique to measure
regional cerebral blood flow as an index of neuronal activity) suggests that episodic
dysfunction of the brainstem, with corresponding effects on the trigeminal system, is
25 confirmed brainstem activation (periaqueductal gray,
dorsal raphe nucleus, and locus coeruleus) at the onset of migraine headaches in a
small sample of patients, and this area may represent an endogenous “migraine
generator.” Whereas the brainstem may be regarded as an anatomic point of
initiation, sensory information in migraine is propagated via higher regions of the
hypothalamus, thalamus, and cortex. Sporadic dysfunction of the nociceptive system
(periaqueductal gray and dorsal raphe nucleus) and the neural control of cerebral
blood flow (dorsal raphe nucleus and locus coeruleus) are hypothesized to trigger
migraine headache via effects of these brain structures on the trigeminovascular
The therapeutic effects of drugs that stimulate 5-HT1
dihydroergotamine, sumatriptan), antagonize 5-HT2
receptors (e.g., cyproheptadine),
prevent 5-HT reuptake (e.g., amitriptyline) or release (e.g., calcium-channel
blockers), or inhibit brainstem serotonergic raphe neurons (e.g., valproate) all lend
support to the hypothesis that 5-HT is an important mediator of migraine.
Furthermore, brainstem nuclei activated during migraine have high densities of
serotonergic neurons. Specific 5-HT receptor subtypes, 5-HT1B and 5-HT1D, are
respectively. These same 5-HT receptor
are the targets of antimigraine drugs such as the triptans and ergot alkaloids.
The genetic basis of migraine is perhaps most effectively understood within the
context of familial hemiplegic migraine. This subtype has been further categorized
into multiple mutation-induced forms with associated genes CACNA1A, ATP1A2,
28 Such genes encode α1 subunits (CACNA1A,
SCN1A) and α2 subunits (ATP1A2), or are linked with glutamate-associated
(SLC1A3) and sodium-bicarbonate-associated (SLC4A4) transporters.
former α-subunit encoders regulate ion passage through calcium and sodium
channels. A further genetic linkage with migraine pathology has been identified in the
Implications of mutations at this level impact neuronal
resting membrane potential, because an identified frameshift mutation negates
29 There is further support for the influence of genetics on migraine
pathology when considering the disproportionate prevalence across gender. Because
prevalence is higher for females, polymorphisms of the estrogen receptor-1 (ESR-1)
gene have been associated with increases in migraine risk.
understanding of the genetic bases for pathology maintain importance, as such
developments impart promise for novel interventional strategies.
Migraine pathology is multifaceted and neuroanatomically diffuse, involving the
brainstem trigeminal nuclei, trigeminovascular afferents, thalamus, hypothalamus,
CTZ, and cortical regions. Therapeutic strategies target the dysfunction in these
regions, the mediation of associated symptomatology, and the modulation of
neuropeptides and neurotransmission.
Quantitative Assessment Instruments
Various patient assessment instruments used to evaluate headache impact include the
Headache Impact Test (HIT-6), Migraine Disability Assessment (MIDAS), and the
Migraine-Specific Quality of Life Questionnaire (MSQ). The HIT-6 utilizes a Likert
scale and evaluates pain, social and cognitive function, and psychological impact.
A higher score on this assessment confers a greater headache impact. Rendas-Baum
33 confirmed validation of this instrument in the context of chronic migraine. The
Migraine Disability Assessment (MIDAS) is a self-administered, 7-item
questionnaire, assessing headache-induced absenteeism, activity limitations, and
headache frequency and intensity. This instrument has demonstrated reliability
34–36 A regression analysis confirmed a significant, independent association
between MIDAS score and pain intensity, headache frequency, and patient age.
MSQ addresses migraine impact across patient social activity, emotional activity,
and the capacity of migraine to prevent activity.
33 With established validity and
37–39 strong correlations between the MSQ and HIT-6 have been confirmed
in the context of chronic migraine.
QUESTION 1: L.P. is a 27-year-old female presenting to her primary care physician (PCP) with a chief
nausea and vomiting, photophobia, and suboccipital pain. Prior episodes have been self-treated with
issue has prompted a visit with the PCP. Physical and neurologic examinations are unremarkable.
What subjective and objective information is consistent with a migraine diagnosis, and how do these
signs/symptoms differ from tension-type headache?
Symptoms reported by L.P. are consistent with migraine. A study by Kelman
addressed migraine location, reporting unilateral character in 67% of study subjects
and bilateral character in nearly 24%.
40 For L.P., migraine location would not be a
differentiating characteristic between migraine and tension headache, because tension
headache is more commonly associated with bilateral character.
described as “severe” and “throbbing,” is consistent with migraine and precipitates
interruptions with daily activity (e.g., absenteeism from work) contrasted with
tension headache which is associated with sensations of tightness.
occurrence of nausea, vomiting, and photophobia more appropriately aligns with
Migraine prevalence is higher in female patients than in male patients,
approximating 17%2 with a cumulative incidence in females of 43%.
prevalence within the range of 18 to 29 years has been reported as nearly 21%.
L.P.’s sex and age would be compatible with prevalence data although it should be
noted that a 28% prevalence statistic for females has been reported in the age range
migraine pathology? What are possible precipitating factors in L.P.?
Factors involved in precipitating migraine should be routinely assessed for all
patients. Assessment should address factors within a patient’s medical history,
medication usage, social history, and environment. L.P.’s medical history is
significant for GAD, she denies the usage of tobacco and illicit substances, she does
report the occasional use of alcohol. Alterations in neurotrophic factors and an
increase in anxiety symptoms have been demonstrated in migraine patients.
evidence imparts value to assess this aspect of L.P.’s medical history. While the
consumption of alcohol should be addressed, the linkage between alcohol
consumption and precipitating migraines is less clear.
of cortical spreading depression, an electrophysiologic factor underlying migraine
pathology, in association with alcohol has been suggested.
L.P., an evaluation of diet may provide useful information in determining migraine
triggers. The evaluation of dietary patterns and quality has yielded disparities,
reporting lower-quality dietary intake in migraine patients.
CASE 58-1, QUESTION 3: Are further diagnostic and laboratory tests indicated in the case of L.P.?
The most important diagnostic evaluations of patients presenting with headache
should be based on a thorough medical history and physical examination. Imaging
(e.g., CT scans, MRI) is generally not required in the context of uncomplicated
The report of symptoms by L.P. is consistent with migraine and is sufficient for
diagnosis. Her symptoms are not associated with a secondary cause, such as trauma
or other injury to the head or neck, and her neurologic examination is unremarkable.
Similarly, without reason to suspect subarachnoid hemorrhage or symptoms
secondary to meningitis, lumbar puncture would not be indicated. Clinical
manifestations that may warrant neurologic imaging to identify artifacts or structural
anomalies include coordination deficits, localized neurologic pathology, sensory
manifestations, an abnormal neurologic examination, or the presence of atypical
47 Further, a change in headache character and headache
onset with advanced age warrants neuroimaging.
CASE 58-1, QUESTION 4: What are the goals of therapy for the management of headache in L.P.?
The approach to management and the treatment objectives for L.P. include
resolving the acute symptoms of pain, nausea, and photosensitivity, educating L.P. on
both prescription and self-care treatment, addressing the contribution of past medical
history and concurrent medication usage to headache episodes, and identifying
CASE 58-1, QUESTION 5: What is the most appropriate recommendation with regard to the use of
acetaminophen to treat headache episodes in L.P.?
L.P. has confirmed self-treatment of headaches with acetaminophen, and in such
instances, it is critical to not only evaluate each patient’s potential for self-care but
also determine whether self-care treatment options can effectively and safely manage
the diagnosis. Reported efficacy of acetaminophen has been mixed. Evidence does
support acetaminophen efficacy in the migraine patient,
acetaminophen with placebo yielded a nearly 20% difference in headache
49 However, a study evaluating the parenteral administration of
acetaminophen for acute management found no significant difference in efficacy
50 Considering L.P.’s report of “variable efficacy” and increase in
headache frequency, she is not an appropriate self-care candidate and continued,
routine use of acetaminophen to manage acute episodes is not recommended.
CASE 58-1, QUESTION 6: What drug-related problems associated with the precipitation or worsening of
migraine should be addressed in L.P.?
Oral contraceptives may either worsen or precipitate migraine attacks in women
without a previous history of this problem.
Incidence may be related to estrogen
52 and/or duration of oral contraceptive use.
53 Alternatively, migraine has been
implicated as an effect of estrogen withdrawal.
54 Such patients may benefit from
contraceptives, or the use of a progestin-only oral contraceptive.
The American Congress of Obstetricians and Gynecologists supports oral
contraceptive use in migraine patients, but recommend avoidance in patients with
tobacco use, in those 35 years or older, and/or in those with the presence of
57 None of these factors are present in L.P.; therefore, oral
contraceptive use may be continued. However, the implications of oral contraceptive
usage and headache should be discussed with L.P. to allow for informed decisionmaking.
Further, consultation with L.P. should address whether GAD is being optimally
managed. The innervation of trigeminovascular circuitry by neurotransmitters (e.g.,
norepinephrine, 5-HT) linked to affective pathology (e.g., anxiety, depression) has
58 and is known to coexist with such patients reporting increased
It is prudent to address anxiety management with L.P. and to
further assess her response to venlafaxine to determine whether dose adjustments or
medication changes are warranted.
CASE 58-1, QUESTION 7: Identify treatment strategies and recommend a medication as a first-line
treatment option for the management of migraine in L.P.
Treatment should be aimed at rapidly resolving symptoms and the restoration of
the patient’s routine activity.
60 Migraines may be managed via a “step” or
61 With a “step” care model, conventional analgesics are
initiated first with the opportunity to progress to using more targeted therapies as
61 A “stratified” care model is based on the character of the migraine and
will further incorporate validated assessment measures into the treatment
In this model, a more targeted, migraine-specific treatment may be
considered first line. A comparison of treatment approaches has favored the
61 The current treatment approach for L.P. has mimicked a “step”
care model, using acetaminophen as a first-line medication.
Triptans (5-HT1B/1D Receptor Agonists)
Triptans, categorized as first (sumatriptan) and second generation (zolmitriptan,
naratriptan, rizatriptan, almotriptan, frovatriptan, and eletriptan), are effective and
well tolerated in acute migraine management and are considered appropriate for
those not responsive to conventional analgesics.
Triptans can be compared on the basis of efficacy, onset, and recurrence potential.
Naratriptan and frovatriptan demonstrate lower recurrence potential whereas the
remaining agents within the class (sumatriptan, rizatriptan, almotriptan, eletriptan,
and zolmitriptan) yield higher efficacy and faster onset.
derivatives, triptans exhibit greater receptor subtype specificity, targeting 5-HT1B
It is important to note that the specific nature of the effect
differs according to receptor subtype. Constriction of the vasculature is mediated via
63 whereas interaction via 5-HT1D antagonizes release of
63 Triptans further diminish neuronal excitability within the
64 and there is evidence of impact on nitric oxide-based
Table 58-1 depicts dosing and pharmacokinetic parameters for the triptans.
Sumatriptan is the prototype of the triptan class and is available in several
formulations, including an oral tablet, nasal spray, and subcutaneous injection (pen
devices and a needle-free solution). A recent analysis confirmed efficacy relative to
placebo across sumatriptan doses and formulations; however, subcutaneous delivery
yielded a more robust analgesic response.
65 Migraine intensity and the character of
associated symptoms (e.g., severity of nausea and vomiting, early-onset nausea)
impact formulation selection. For patients who are nauseated and prone to vomit
during an acute attack, the subcutaneous and intranasal dosage forms are preferred.
Both formulations have a rapid onset of effect. Reduction in headache intensity is
reported within 10 minutes after subcutaneous injection and within 15 minutes after
administration of the nasal spray.
41 Comparisons of orally administered sumatriptan
(doses of 25, 50, and 100 mg) have yielded higher efficacy rates relative to placebo
in achieving headache relief at 2 hours.
66 Higher sumatriptan doses of 50 and 100 mg
were superior to placebo in achieving headache relief at 4 hours.
Comparative efficacy studies with sumatriptan have yielded mixed results.
Subcutaneous sumatriptan is more effective and
faster acting than dihydroergotamine (DHE) nasal spray.
subcutaneous DHE, subcutaneous sumatriptan is more effective at 1 and 2 hours, but
the two treatments are equally effective at 3 and 4 hours.
recurrence rates at 24 hours favored subcutaneous DHE.
of these agents supports efficacy of sumatriptan for both headache relief and the relief
of associated symptoms (e.g., nausea) 60 minutes after dosing.
been reported for comparison with almotriptan
efficacy being reported versus eletriptan
Although sumatriptan is well tolerated, there is some variability in the adverse effect
profile across different formulations. In general, both oral and intranasal sumatriptan
formulations are associated with a low incidence of systemic adverse events. Oral
administration of sumatriptan has been associated with adverse effects including
dizziness, fatigue, nausea, and vomiting,
72 whereas intranasal administration may
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