 |
|
Effectiveness of Intranasal
Zolmitriptan in Acute Cluster Headache
A Randomized, Placebo-Controlled, Double-blind
Crossover Study
Elizabeth
Cittadini, MD; Arne May, MD; Andreas
Straube, MD; Stefan Evers, MD; Gennaro
Bussone, MD; Peter J. Goadsby, MD, PhD
Arch Neurol. 2006;63:1537-1542. Published
online September 11, 2006 (doi:10.1001/archneur.63.11.nct60002)
ABSTRACT
|
|
Background Cluster headache is a form of primary
headache in which attacks are rapid in onset with very
severe pain. The mainstays of acute therapy are inhaled
oxygen and sumatriptan succinate injection.
Objective To evaluate zolmitriptan nasal spray in
the acute treatment of cluster headache.
Methods Ninety-two patients, aged
40 ± 10 years (mean ± SD) (80 men and
12 women), with International Headache Society–defined
cluster headache were randomized into a
placebo-controlled, double-blind crossover study.
Patients treated 3 headache attacks using placebo for 1
attack, 5 mg of zolmitriptan nasal spray (ZNS5) for 1 attack,
and 10 mg of zolmitriptan nasal spray for 1 attack. The
primary end point was headache relief at 30 minutes,
defined as reduction from moderate, severe, or very
severe pain to no or mild pain. The study was approved by
the appropriate ethics committees.
Results Sixty-nine patients were available for an
intention-to-treat analysis. The 30-minute headache
relief rates were placebo, 21%; ZNS5, 40%; and ZNS10,
62%. Modeling the response as a binary outcome, the Wald
test was significant for the overall regression ( 21 = 29.4;
P<.001), with both ZNS5 and ZNS10 giving
significant effects against placebo. Headache relief rates
for patients with episodic cluster headache were 30% for
placebo, 47% for ZNS5, and 80% for ZNS10, while
corresponding rates for patients with chronic cluster
headache were 14%, 28%, and 36%, respectively.
Zolmitriptan was also well tolerated.
Conclusion Five-milligram and 10-mg doses of
zolmitriptan intranasal spray are effective within 30
minutes and well tolerated in the treatment of acute
cluster headache.
Trial Registration controlled-trials.com Identifier
ISCRTN27362692.
INTRODUCTION
Cluster headache (CH) is the most painful form of primary
headache, typically characterized by attacks of usually excruciating
unilateral pain lasting 15 to 180 minutes.1
Because of the very severe nature of CH, acute-attack
treatments need to work swiftly.2
The best placebo-controlled evidence for acute-CH
treatment is for sumatriptan succinate by intranasal3
and subcutaneous4-5
administration. Limited evidence exists to treat acute
attacks of CH with oxygen inhalation,6-7
intranasal lidocaine,8
and intranasal dihydroergotamine mesylate.9
Intranasal dihydroergotamine was reported to be better
than placebo, but the time to onset of a response was not
defined and the study used pre–International Headache
Society diagnostic criteria.9
Inhalation of oxygen is effective and safe but may
be impractical for some patients. Oral zolmitriptan
has been demonstrated to be effective in acute episodic
CH,10
albeit at higher doses than normally used in
migraine.11
There remains a considerable unmet need in CH for
therapies with a clear evidence base.
Zolmitriptan is a serotonin, 5-HT-1B/1D, receptor
agonist that has actions at the peripheral12
and central ends of the trigeminovascular system.13-15
Zolmitriptan is an effective, well-tolerated treatment of
acute migraine,11
with oral and intranasal formulations.16
The newly developed intranasal formulation has an onset of
action that is earlier than the oral formulation,17
and there is clear evidence for intranasal
absorption.18
A comparison of the pharmacokinetics of intranasal
zolmitriptan with intranasal sumatriptan suggests that
intranasal zolmitriptan should be effective in acute CH.16
A preliminary, single-blind study has suggested
zolmitriptan by the intranasal route may be effective in
acute CH.19
In the present study, we aimed to investigate whether
intranasal zolmitriptan is superior to placebo in the
acute treatment of CH attacks lasting at least 45 minutes
using the primary outcome measure of headache response at
30 minutes. We wished to test 2 doses, 5 and 10 mg, and
take advantage of the clinical presentation of CH with
reproducible attacks over short periods, and bearing in
mind its relatively rarity, to conduct a crossover study.
We have presented the results in preliminary form.20
METHODS
PATIENTS
Patients, men or women between 18 and 65 years of age, with
an established diagnosis of CH according to the
International Headache Society criteria,1
were recruited by 5 study centers (3 in Germany, 1 in
Italy, and 1 in the United Kingdom). Patients were
required to have CH attacks lasting at least 45 minutes
when untreated. Patients should have used zolmitriptan in
the past; zolmitriptan-naïve patients were included if,
in the opinion of the investigator, it was safe to do so.
We excluded patients unsuitable for zolmitriptan tablet
or nasal spray use in the country in which the study was
being conducted according to the drug label or regulatory
approved use in that country. We also excluded patients
with more than 2 risk factors for cardiovascular disease,
patients using regular ergotamine derivatives or
analgesics, and patients with an ears, nose, and throat
disorder that would preclude the use of intranasal
zolmitriptan.
DESIGN
This was a randomized, double-blind, 3-attack crossover
study of 5-mg or 10-mg zolmitriptan nasal spray and
matching placebo. Cluster headache is relatively
uncommon, so a crossover study facilitated recruitment as
well as provided homogeneity for comparisons between
treatments and placebo. The disadvantage of a carryover
effect in a crossover design is minimal because the
treatment has a short half-life relative to the interval
we specified and the interaction is easily modeled in the
analysis used. Patients were asked to treat 3 attacks, at
least 24 hours apart, with study medicine. They
were instructed to grade their pain on an ordinal categorical
(5-point) scale of none, mild, moderate, severe, or very
severe21
and to apply 1 study dose in the contralateral nostril
when the headache had at least reached a moderate
severity. Subsequent assessments were at 5, 10, 15,
and 30 minutes. Escape medication was allowed at 30
minutes postdose, using oxygen or an analgesic but not a
triptan or ergotamine derivative. The sponsor provided
the study medication, matching placebo, and randomization
schedule; the latter was kept by respective pharmacies
until the study was completed.
EFFICACY ASSESSMENTS
The primary protocol-specified outcome measure was headache
response at 30 minutes, defined as a reduction in headache
from moderate, severe, or very severe to no or mild pain.
Secondary outcome measures included the percentages of
patients headache free at 30 minutes and rate of relief
of associated symptoms. Associated symptoms, such as
vomiting, nausea, photophobia, phonophobia, lacrimation,
nasal congestion, other autonomic features, and
restlessness and agitation, were recorded immediately
prior to treatment and at 30 minutes. Finally, adverse
events were assessed by comparison of tolerability of
nasal zolmitriptan to placebo.
STATISTICAL ANALYSIS
Based on the effect of sumatriptan nasal spray3
and our clinical experience of what would be a meaningful
effect, we planned for a treatment difference between
placebo and active treatment of 20%. We estimated that we
would require 100 patients to have 65 evaluable for at
least 1 attack with a power of 80% (1- ) and an  of 5% for
the primary end point. Initial power was calculated with
ties to be discarded as if to use the McNemar test.22
The outcome data were to be treated as binary. The ties
were estimated from the results of a crossover study of
subcutaneous sumatriptan vs placebo4
and allowed for some difference in therapeutic responses
seen between sumatriptan injections and the nasal spray in
migraine.23
Our planned analysis specifically allowed for the
dichotomous outcome and used a generalized linear model
and logistic regression approach to determine the effect
of active treatment and treatment order, sex, site, and
CH type (ie, episodic vs chronic CH).1
Considering that the 3 attacks are not strictly
independent because the patients remain the same, a
multilevel multivariate analysis24
was performed using the software developed by the
Multilevel Project, MlwiN.25
To avoid multiple comparisons, we did not test the effect
of study treatment on associated symptoms, preferring to
report the numerical outcome.
APPROVAL
The appropriate institutional review boards or ethics
committees of the participating sites reviewed and
approved the protocol prior to the study commencing. All
patients gave informed consent before entering the study.
The study protocol was initially written by 1 of us
(P.J.G.). The pharmaceutical company provided the study
medication but, consistent with recent guidelines,26
had no influence on or involvement in the conduct of the
study, the analysis, or publication of the results. As
per our protocol, the sponsor was provided with a copy of
the manuscript.
RESULTS
A total of
92 patients was recruited, 80 men and 12 women, with a
mean ± SD age of 40 ± 10 years,
between June 12, 2003, and May 24, 2005.
DISPOSITION OF PATIENTS
Of the 92 patients recruited, 17 came to the end of the
bout, which is to say their attacks stopped before
completing the study; 4 of these treated the first
attack, and 4 treated the first and second attacks. Eight
patients withdrew before treating any attacks. Three
patients withdrew after treating the first attack, 2 of
these without a clear reason and 1 because of an adverse
effect. Six patients were completely lost to follow-up
and whether they treated their attacks was not clear. We
have regarded them as though they did not treat any
attacks. The average duration of an untreated attack was
45 minutes. Use of escape medication before 30 minutes
after treatment was reported in 1 attack, which was
scored as a treatment failure (Figure
1).
|
|
|
| Figure 1. Disposition of patients in
the study.
| | |
CLINICAL FEATURES OF STUDY COHORT
The mean ± SD duration of CH history was
12 ± 7 years. Fifty-nine patients had episodic
CH and 33 had chronic CH. The mean ± SD bout
length of the patients with episodic CH was
8 ± 6 weeks. The mean ± SD attack
duration at recruitment was reported by the patients to
be 95 ± 43 minutes. Sixty-seven patients had
previously used subcutaneous sumatriptan, 40 patients had
used intranasal sumatriptan, 18 patients had used oral
zolmitriptan, and 72 patients had used oxygen (Table
1).
|
|
|
| Table 1. Demographic Data and CH
Characteristics of Included Patients
| | |
EFFICACY
The primary end point of the study was the combined (attacks
1, 2, and 3) headache response rate at 30 minutes compared
with placebo. The Wald test was significant for the
overall regression (21 = 29.4;
P<.001), with the treatment term and CH type
being significantly different from zero. There was no
significant effect of treatment order or patient sex.
Efficacy Results for the Cohort as a
Whole
In total, 65 attacks were treated with 5 mg of zolmitriptan
nasal spray; 63 attacks, with 10 of mg zolmitriptan nasal
spray; and 61 attacks, with placebo. In the attacks
treated with 5 mg of zolmitriptan nasal spray, 27
patients (42%) reported headache relief at 30 minutes,
and in the attacks treated with 10 mg of zolmitriptan
nasal spray, 38 patients (61%) reported headache relief
at 30 minutes, compared with 14 patients (23%) who treated
an attack with placebo (P = .002) (Figure
2). Eighteen patients (28%) were pain free at 30
minutes when treated with 5 mg of zolmitriptan nasal
spray and 31 patients (50%) were pain free at 30 minutes
when treated with 10 mg of zolmitriptan nasal spray,
compared with 10 patients (16%) who treated an attack
with placebo (P = .003). At 15 minutes after
treatment, 1.6% of patients using placebo, 9% using 5 mg
of zolmitriptan nasal spray, and 19% using 10 mg of
zolmitriptan nasal spray reported headache relief (Table
2).
|
|
|
Figure 2. Efficacy results for the
cohort as a whole. Headache response, a reduction
of headache intensity from very severe, severe, or
moderate to mild or no pain, and pain-free rates
(no pain) at 30 minutes after treatment with
zolmitriptan vs placebo (A). * P<.002;
 ,
P<.003. Data for headache response (B)
and pain-free rates (C) are demonstrated as they
cumulate with time from treatment at time zero to
30 minutes postdose.
| | |
|
|
|
| Table 2. Efficacy Data From Early Points
for Headache Relief and Headache Free
| | |
Episodic vs Chronic CH
Of the treated cohort, 40 patients had episodic CH and 29
had chronic CH, with a total of 104 attacks treated by
the episodic CH group and 85 by the chronic CH group. For headache relief at 30 minutes in the episodic CH group,
10 attacks (30%) of the 33 treated with placebo had a response,
while 17 (47%) of 36 had relief using 5 mg of zolmitriptan nasal
spray and 28 (80%) of 35 had relief using 10 mg of zolmitriptan
nasal spray. In comparison, for the patients with
chronic CH, 4 (14%) of 28 who treated attacks with
placebo had relief, 8 (28%) of 29 had relief using 5 mg
of zolmitriptan nasal spray, and 10 (36%) of 28 had
relief using 10 mg of zolmitriptan nasal spray (Figure
3).
|
|
|
| Figure 3. Comparison of headache
relief rates (moderate, severe, or very severe
pain going to no or mild pain) at 30 minutes after
treatment (ordinate percentage) for placebo, 5 mg
of zolmitriptan nasal spray, and 10 mg of
zolmitriptan nasal spray between episodic and
chronic cluster headache.
| | |
Associated Symptoms
To evaluate the associated symptoms, only patients who had
the symptom immediately before treatment were included in
the analysis. Conjunctival injection/lacrimation, nasal
congestion/rhinorrhea, and ptosis/eyelid edema were the
most frequently mentioned associated symptoms. In the
attacks treated with zolmitriptan nasal spray,
numerically more patients reported relief from associated
symptoms at 30 minutes (Figure
4).
|
|
|
| Figure 4. Percentage of patients
reporting improvement of associated symptoms while
taking zolmitriptan and placebo at 30 minutes
compared with baseline. Only patients with the
symptom at baseline were included. Because of
multiple-comparison issues, no statistical
analysis was performed.
| | |
Escape Medication
The frequency of the use of escape medication was lower in
the zolmitriptan-treated attacks compared with those
treated with placebo (placebo, 30 [50%]; 5 mg of
zolmitriptan nasal spray, 23 [35%]; and 10 mg of
zolmitriptan nasal spray 17 [27%]).
Tolerability
No serious adverse events were reported in either the
zolmitriptan-treated or placebo-treated attacks. The
important adverse effects that led to withdrawal occurred
in a patient treated with 5 mg of zolmitriptan nasal
spray and were shortness of breath, vomiting, and
rheumatic pain.
COMMENT
The data demonstrate that 5 or 10 mg of intranasal
zolmitriptan are better than placebo in the acute treatment of CH at
30 minutes posttreatment. The very minimal dropout rate and low
number of adverse events reported suggest that intranasal
zolmitriptan is well tolerated in patients treating acute
CH. The data provide evidence that zolmitriptan nasal
spray can be used as a first-line abortive therapy, along
with sumatriptan nasal spray or inhaled oxygen, in the
management of CH.
Given the relative rarity of CH, we chose a crossover
approach to study this patient group. This approach has
the advantages of providing both patients and health care
professionals with the practical knowledge of how the
active medicine compares with placebo within an
individual. Similarly, it enables intraindividual
comparison of adverse events so that the balance of
adverse effect vs efficacy can be directly assessed.
Given that CH attacks occur frequently, it is possible to
treat 3 attacks over a short period, rendering it likely
that the attacks are relatively homogenous. Dropouts are
an important consideration in a crossover study, and we
had few. This is likely because the patient group was
well motivated and, in part, because our centers have a
close working relationship with the patient groups such
that the study was explained to them and their
participation agreed before it commenced. An issue that
cannot be avoided in crossover studies is that the
observations can never be truly independent since they
come from the same individuals. The multilevel analysis
approach that we have used24,
27
explicitly accounts for this problem and is a great
advantage in this area. A further issue in our study is
that the patients were all recruited at specialist
centers. This must limit the generalizability of the
result, although it might be argued that the patients
attending such centers are more likely to be refractory
to treatment and thus the results herein are possibly
conservative.
The current gold-standard treatment of acute CH is
subcutaneous sumatriptan. It is clearly effective4-5
and well tolerated.28
It has been shown in a similar study to the current one, a
single-way crossover study, that 20 mg of sumatriptan
succinate nasal spray is also effective in acute CH at 30
minutes.3
The new data are consistent with this. It had been
previously reported that zolmitriptan when administered
orally at the 10-mg dose was effective in acute
CH.10
Given the pharmacokinetics of the zolmitriptan spray, it
could be predicted that both the 5- and 10-mg sprays would
be effective,29
and that is what has been seen. Given that there are good
safety data for zolmitriptan's use in a daily dose of 15
mg,11
albeit not in CH but in migraine, it seems a possible
advantage that patients with CH may be able to use three
5-mg doses in 24 hours. For the patient with CH not
responding well to oxygen and limited to 2 sumatriptan
injections per 24 hours, this seemingly small advantage,
day after day, will accrue. Such an approach must be made
with caution since we have no long-term data in CH and we
have no systematic information collected as to what the
propensity for rebound headache with regular, more
frequent use may be.30
Given the long-term safety data for subcutaneous
sumatriptan, it seems unlikely that a specific problem
will emerge with zolmitriptan in CH.
AUTHOR INFORMATION
Correspondence: Peter J. Goadsby, MD, PhD,
Institute of Neurology, The National Hospital for
Neurology and Neurosurgery, Queen Square, London WC1N
3BG, United Kingdom (peterg{at}ion.ucl.ac.uk
).
Accepted for Publication: June 28, 2006.
Published Online: September 11, 2006
(doi:10.1001/archneur.63.11.nct60002).
Author Contributions: Drs Cittadini and Goadsby made the
initial analysis of the data and wrote the first draft of
the manuscript. Study concept and design: May,
Bussone, and Goadsby. Acquisition of data:
Cittadini, May, Straube, Evers, and Goadsby. Analysis
and interpretation of data: Evers and Goadsby. Drafting
of the manuscript: Evers and Goadsby. Critical
revision of the manuscript for important intellectual
content: Cittadini, May, Straube, Evers, Bussone, and
Goadsby. Statistical analysis: Cittadini and
Goadsby. Obtained funding: Goadsby. Administrative,
technical, and material support: Straube, Evers, and
Goadsby. Study supervision: Evers, Bussone, and
Goadsby.
Financial Disclosure: None reported.
Funding/Support: AstraZeneca supported this work but did
not initiate, design, or analyze the study; interpret the
data; or have any role in the writing of the
manuscript.
Author
Affiliations: Institute of Neurology, The National Hospital for
Neurology and Neurosurgery, Queen Square, London, England (Drs
Cittadini and Goadsby); Department of Neurology, University of
Hamburg, Hamburg, Germany (Dr May); Department of Neurology,
University of Munich, Munich, Germany (Dr Straube); Department of
Neurology, University of Münster, Münster, Germany (Dr Evers);
Department of Neurology, "C. Besta" Neurological Institute, Milan,
Italy (Dr Bussone).
REFERENCES
|
|
1.
Headache Classification Committee of the International Headache
Society. The International Classification of Headache Disorders
(second edition). Cephalalgia. 2004;24(suppl 1):1-160. ISI
2.
Bahra A, May A, Goadsby PJ. Cluster headache: a prospective clinical
study in 230 patients with diagnostic implications.
Neurology. 2002;58:354-361. FREE FULL TEXT
3.
van Vliet JA, Bahra A, Martin V, et al. Intranasal sumatriptan in
cluster headache—randomized placebo-controlled double-blind study.
Neurology. 2003;60:630-633. FREE FULL TEXT
4.
Treatment of acute cluster headache with sumatriptan: the
Sumatriptan Cluster Headache Study Group. N Engl J Med.
1991;325:322-326. ABSTRACT
5.
Ekbom K, Monstad I, Prusinski A, Cole JA, Pilgrim AJ, Noronha D.
Subcutaneous sumatriptan in the acute treatment of cluster headache:
a dose comparison study. Acta Neurol Scand. 1993;88:63-69. ISI |
PUBMED
6.
Fogan L. Treatment of cluster headache: a double blind comparison of
oxygen vs air inhalation. Arch Neurol. 1985;42:362-363. ABSTRACT
7.
Kudrow L. Response of cluster headache attacks to oxygen inhalation.
Headache. 1981;21:1-4. FULL
TEXT | ISI |
PUBMED
8.
Robbins L. Intranasal lidocaine for cluster headache.
Headache. 1995;35:83-84.
FULL
TEXT | ISI |
PUBMED
9.
Andersson PG, Jespersen LT. Dihydroergotamine nasal spray in the
treatment of attacks of cluster headache. Cephalalgia.
1986;6:51-54. FULL
TEXT | ISI |
PUBMED
10.
Bahra A, Gawel MJ, Hardebo J-E, Millson D, Brean SA, Goadsby PJ.
Oral zolmitriptan is effective in the acute treatment of cluster
headache. Neurology. 2000;54:1832-1839. FREE FULL TEXT
11.
Palmer KJ, Spencer CM. Zolmitriptan. CNS Drugs.
1997;7:468-478. ISI
12.
Martin GR, Robertson AD, MacLennan SJ, et al. Receptor specificity
and trigemino-vascular inhibitory actions of a novel
5-HT1B/1D receptor partial agonist, 311C90
(zolmitriptan). Br J Pharmacol. 1997;121:157-164. FULL
TEXT | ISI |
PUBMED
13.
Goadsby PJ, Edvinsson L. Peripheral and central trigeminovascular
activation in cat is blocked by the serotonin (5HT)-1D receptor
agonist 311C90. Headache. 1994;34:394-399. FULL
TEXT | ISI |
PUBMED
14.
Goadsby PJ, Hoskin KL. Inhibition of trigeminal neurons by
intravenous administration of the serotonin (5HT)1B/D
receptor agonist zolmitriptan (311C90): are brain stem sites a
therapeutic target in migraine? Pain. 1996;67:355-359. FULL
TEXT | ISI |
PUBMED
15.
Goadsby PJ, Knight YE. Direct evidence for central sites of action
of zolmitriptan (311C90): an autoradiographic study in cat.
Cephalalgia. 1997;17:153-158. FULL
TEXT | ISI |
PUBMED
16.
Goadsby PJ, Yates R. Zolmitriptan intranasal: a review of the
pharmacokinetics and clinical efficacy. Headache.
2006;46:138-149. FULL
TEXT | ISI |
PUBMED
17.
Charlesworth BR, Dowson AJ, Purdy A, Becker WJ, Boes-Hansen S,
Farkkila M. Speed of onset and efficacy of zolmitriptan nasal spray
in the acute treatment of migraine: a double-blind,
placebo-controlled, dose-ranging study versus zolmitriptan tablet.
CNS Drugs. 2003;17:653-667. FULL
TEXT | ISI |
PUBMED
18.
Zingmark P-H, Yates R, Hedlund C, Kagedal M. True nasopharyngeal
absorption of zolmitriptan following administration of zolmitriptan
nasal spray [abstract]. Eur J Neurol. 2003;10(suppl 1):76.
19.
Mathew NT, Kailasam J, Seifer T, Bouton T. Zolmitriptan (Zomig)
nasal spray in cluster headache attacks; a single-blind
observation—a preliminary report [abstract]. Headache.
2004;44:483.
20.
Cittadini E, May A, Straube A, Evers S, Bussone G, Goadsby PJ.
Zolmitriptan nasal spray is effective and well tolerated in the
acute treatment of cluster headache: a double-blind
placebo-controlled crossover study [abstract]. Eur J Neurol.
2005;12(suppl 2):202. FULL
TEXT
21.
Pilgrim AJ. Methodology of clinical trials of sumatriptan in
migraine and cluster headache. Eur Neurol. 1991;31:295-299. ISI |
PUBMED
22.
Siegel S. Non-parametric Statistics for the Behavioural
Sciences. Tokyo, Japan: McGraw-Hill Kogakusha; 1956.
23.
Tfelt-Hansen P. Efficacy and adverse events of subcutaneous, oral,
and intranasal sumatriptan used for migraine treatment: a systematic
review based on number needed to treat. Cephalalgia.
1998;18:532-538. FULL
TEXT | ISI |
PUBMED
24.
Snijders TAB, Bosker RJ. Multilevel Analysis: An Introduction to
Basic and Advanced Multilevel Modelling. London, England: Sage
Publications; 1999.
25.
Multilevel modelling. Center for Multilevel Modelling Web site. http://www.mlwin.com/. Accessed
January 24, 2006.
26.
Rosenberg RN, Aminoff M, Boller F, et al. Reporting clinical trials:
full access to all the data. Neurology. 2002;58:347-348. FREE FULL
TEXT
27.
Yang M, Goldstein H, Heath A. Multilevel models for repeated binary
outcomes: attitudes and voting over the electoral cycle. J R Stat
Soc [Ser A]. 2000;163:49-62.
FULL
TEXT | ISI
28.
Goadsby PJ. Cluster headache and the clinical profile of
sumatriptan. Eur Neurol. 1994;34(suppl):35-39. ISI |
PUBMED
29.
Yates R, Nairn K, Dixon R, Kemp JV, Dane AL. Pharmacokinetics, dose
proportionality, and tolerability of single and repeat doses of a
nasal spray formulation of zolmitriptan in healthy volunteers. J
Clin Pharmacol. 2002;42:1244-1250. ABSTRACT
30.
Paemeleire K, Bahra A, Evers S, Matharu MS, Goadsby PJ.
Medication-overuse headache in cluster headache patients.
Neurology. 2006;67:109-113. FREE FULL TEXT
SECTION
EDITOR: IRA SHOULSON, MD
RELATED
ARTICLE
This Month in Archives of
Neurology
Arch Neurol. 2006;63:1523-1524.
FULL
TEXT
|
