VIEWS & REVIEWS
Acute and preventive pharmacologic
George J. Francis, BSc
Werner J. Becker, MD
Tamara M. Pringsheim,
MD
Address correspondence and
reprint requests to Dr. Tamara
Pringsheim, Department of
Clinical Neurosciences, 2888
Shaganappi Trail NW, Calgary,
Alberta, T3B 6A8, Canada
tmprings@ucalgary.ca
Supplemental data at
www.neurology.org
treatment of cluster headache
ABSTRACT
Cluster headache (CH) is a rare and disabling primary headache disorder. CH attacks are unilateral,
short, severe headaches associated with ipsilateral autonomic symptoms that occur in a periodic
fashion. We provide a systematic review and meta-analysis of existing trials of pharmacotherapy for
CH and evidence-based suggestions for acute abortive treatment and preventive therapy for cluster
headache. Prospective, double-blind, randomized controlled trials of any pharmacologic agent for the
symptomatic relief or prevention of CH were included in this evidence-based review. The main out-
comes considered were headache response and pain-free response at 15 and 30 minutes for acute
treatment trials, and the cessation of CH attacks within a specific time period or the number of days
on which CH attacks occurred for preventive trials. Twenty-seven trials were included in the analysis.
The American Academy of Neurology quality criteria were used to assess trial quality and to grade
advisements. Based on the evidence, for acute treatment of CH, Level A advice can be given for
subcutaneous sumatriptan 6 mg, zolmitriptan nasal spray 5 mg and 10 mg, and 100% oxygen 6 –12
L/min. Level B advice can be given for sumatriptan nasal spray 20 mg and oral zolmitriptan 5 mg and
10 mg. For the prevention of CH, Level B advice can be given for intranasal civamide 100 ␮g daily and
suboccipital steroid injections, and Level C advice can be given for verapamil 360 mg, lithium 900 mg,
and melatonin 10 mg. Neurology® 2010;75:463–473
GLOSSARY
AAN ⫽ American Academy of Neurology; AE ⫽ adverse event; CH ⫽ cluster headache; CI ⫽ confidence interval; NS ⫽ nasal
spray; OR ⫽ odds ratio; RCT ⫽ randomized controlled trial; SC ⫽ subcutaneous; SCHSG ⫽ Sumatriptan Cluster Headache
Study Group.
The International Classification of Headache Disorders, 2nd edition,1 defines CH as at least 5
severe to very severe unilateral headache attacks, lasting 15 to180 minutes untreated. Attacks
are accompanied by ipsilateral autonomic symptoms, restlessness, or agitation. Attack fre-
quency ranges from 1 every other day to 8 per day. There are 2 types of CH: episodic CH and
chronic CH. Patients with episodic CH have attacks that occur in series lasting weeks or
months separated by remission periods usually lasting months or years. Patients with chronic
CH have attacks occurring for more than 1 year without remission or with remissions lasting
less than 1 month. A total of 10% to 15% of patients with CH have chronic CH.1
The pathogenesis of CH is incompletely understood, although hypothalamic dysfunction is
suspected.2 There is clinical evidence for altered biologic rhythms in patients with CH, and the
timing of attacks relates to the sleep-wake cycle in many patients.3 The uncertainty regarding
the pathogenesis of CH renders it difficult to aim treatments toward a specific target.
Treatment of CH has 2 strategies: symptomatic therapy taken at the time of an attack, and
preventive therapy taken when the cluster bout begins to prevent further attacks. As CH causes
significant disability, the investigation of evidence-based medical treatments is warranted. We
present a systematic review and meta-analysis of treatment trials for CH and evidence-based
advice for acute and preventive treatments of CH.
Editor’s Note: This article reflects the opinions of the authors and, unlike AAN evidence-based reviews, has not been endorsed by the AAN.
From the Department of Clinical Neurosciences, University of Calgary, Canada.
Disclosure: Author disclosures are provided at the end of the editorial.
Copyright © 2010 by AAN Enterprises, Inc. 463
 OBJECTIVES/CLINICAL QUESTIONS
• Which acute treatments for CH are effective in
reducing headache severity?
• Which preventive treatments are effective in re-
ducing CH attacks?
CRITERIA FOR CONSIDERING STUDIES Stud-
ies were required to be prospective, double-blind,
parallel-group or crossover, randomized controlled
trials (RCTs) of any medication vs placebo or an-
other drug, for the symptomatic relief or prevention
of CH. Study participants were 18 or older with ei-
ther episodic CH or chronic CH.
For efficacy analysis, the following main out-
comes were considered:
1. Headache response at 15 or 30 minutes, defined
as a reduction in headache from moderate, severe,
or very severe to mild or no pain (symptomatic
trials)
2. Pain-free response at 15 or 30 minutes (symp-
tomatic trials)
3. Cessation of CH attacks within a specific time
period (preventive trials)
4. Number of days on which a CH attack occurred
(preventive trials)
For the analysis of data on adverse events (AEs),
we considered the overall number of patients report-
ing AEs.
SEARCH METHODS FOR IDENTIFICATION OF
STUDIES MEDLINE (1950 to June 2009) and
EMBASE (1980 to June 2009) databases were
searched for double-blind RCTs (see appendix e-1
on the Neurology® Web site at www.neurology.org
for detailed search strategy).
METHODS OF REVIEW Two reviewers (T.P. and
G.J.F.) independently screened titles and abstracts
for trials fulfilling inclusion criteria. Data were ab-
stracted independently by the reviewers and con-
firmed for accuracy. Discrepancies between reviewers
were resolved by discussion.
The studies were evaluated using quality criteria
developed by the American Academy of Neurology
(AAN)4 (see appendix e-2). Suggestions were made
according to the AAN grades for classification of rec-
ommendations (see appendix e-3).
SUMMARIZING THE RESULTS Meta-analysis was
performed by treatment type. Odds ratios (OR) were
calculated with 95% confidence intervals (CI). ORs
from multiple studies were tested for homogeneity
using the ␹2 test and by calculating the I2 statistic. If
study estimates were homogenous, they were com-
464 Neurology 75 August 3, 2010
bined using a fixed-effects model. When studies with
heterogeneous results were clinically similar, the
study estimates were combined using a random-
effects model. Clinical heterogeneity was assessed by
looking at trial and patient characteristics, and out-
come measures. Clinically heterogeneous studies
were not statistically combined.
DESCRIPTION OF STUDIES A total of 1,547 ab-
stracts were found by the combined searches (see the
figure for flow diagram). A total of 1,499 abstracts
did not meet inclusion criteria. Forty-nine full-text
articles were reviewed. Twenty-three did not meet
inclusion criteria (see appendix e-4). The remaining
26 studies were included in the analysis: 11 on acute
treatment of CH,5-15 14 on prevention of CH,16-29
and 1 on both acute treatment and prevention of
CH.30 The MEDLINE search was re-executed prior
to final revision of the manuscript (February 1,
2010). This revealed 22 more abstracts published
since the original search. One abstract met inclusion
criteria and was included in the study,31 giving a total
of 27 studies in the analysis.
RCTs for acute treatment of CH had similar inclu-
sion criteria. Studies included patients 18 to 65 years of
age, with a history of episodic CH or chronic CH, and
attacks of 45 minutes minimum duration untreated.
Trials using triptans excluded patients with heart dis-
ease, uncontrolled hypertension, or concomitant use of
ergotamine or monoamine oxidase inhibitors. The
most common endpoints used were the headache re-
sponse or pain-free response at 30 minutes. A summary
of the trial characteristics, methodologic flaws, and re-
sults can be seen in table 1.
Inclusion criteria for RCTs studying prevention of
CH included patients with at least 1 cluster period last-
ing at least 1 month prior to the study. Patients were in
a cluster period for no more than 10 days, with an ex-
pected remainder of cluster period of no less than 20
days. Specifically excluded were patients with cardiovas-
cular, pulmonary, hepatic, or renal disease, as well as
patients who were pregnant or currently taking prophy-
lactic CH medication. The primary endpoint for stud-
ies was a reduction in the number of headaches during
the period of study medication use, in comparison to a
run-in period with no CH prophylaxis. A summary of
the trial characteristics, methodologic flaws, and results
can be seen in table 2.
RESULTS Acute treatment. Which acute treatments
for CH are effective in reducing pain? (See table 3 for
an advice summary.)
Sumatriptan. Three RCTs compare sumatriptan
to placebo, all meeting AAN Class I criteria.5-7 Ek-
bom et al.5 and The Sumatriptan Cluster Head-
Figure PRISMA flow diagram
ache Study Group6 (SCHSG) performed crossover
studies of sumatriptan 6 mg subcutaneous injec-
tion (SC) vs placebo for 2 attacks. The study by
Ekbom et al. also assessed sumatriptan 12 mg. van
Vliet et al.7 performed a 2-group crossover study
of sumatriptan 20 mg nasal spray (NS) vs placebo
for 2 CH attacks. Only the Ekbom et al. and the
SCHSG studies were combined statistically, as
both these trials used sumatriptan SC.
Sumatriptan SC 6 mg or 12 mg. Headache response at
15 minutes: the 2 studies included 258 CH at-
tacks.5,6 Meta-analysis using a random effects model
gave a summary OR of 6.22 in favor of sumatriptan
(95% CI 3.61–10.72, p ⬍ 0.00001). No difference
was found between the 2 sumatriptan doses. The
most common AEs reported were injection site reac-
tions, nausea and vomiting, dizziness, fatigue, and
paraesthesias.
Sumatriptan NS 20 mg. Headache response at 30 min-
utes: this crossover study included 83 patients. Two at-
tacks were treated with sumatriptan 20 mg NS or
placebo.7 Sumatriptan was superior to placebo, as 57%
of patients reported headache relief with sumatriptan
compared to 26% with placebo (p ⫽ 0.002). The most
frequent AE reported was a bitter taste following use of
the nasal spray in 21% of patients.
Sumatriptan SC should be offered to patients for
acute treatment of CH (Level A). Sumatriptan NS
should be considered for acute treatment of CH
(Level B).
Zolmitriptan. Three RCTs compare zolmitriptan
to placebo, all meeting AAN Class I criteria.8-10
Two are crossover studies 8,9 comparing zolmi-
triptan NS 5 mg and 10 mg to placebo. The
other10 compares oral zolmitriptan 5 mg and 10
mg to placebo.
Zolmitriptan NS, 5 and 10 mg. Headache response at
30 minutes: Both studies used a primary efficacy
analysis of headache response at 30 minutes, includ-
ing 451 CH attacks.8,9 Meta-analysis using a random
effects model found a summary OR of 5.03 (95% CI
2.81–9.01, p ⬍ 0.00001) for zolmitriptan 10 mg
Neurology 75 August 3, 2010 465
466
Table 1 Summary of results: The effect of acute treatment of cluster headache

Neurology 75
Reference Quality
no. No. assessment Intervention Primary outcome Dropouts Results p Value Quality criteria unfulfilled

5 157 AAN Class I Sumatriptan 6 or 12 mg SC vs Headache response at 10 min 134 patients treated 2 Headache response: sumatriptan 12 mg 0.05
placebo; 2 attacks attacks 63%; sumatriptan 6 mg 49%; placebo 25%

6 49 AAN Class I Sumatriptan 6 mg SC vs Headache response at 15 min 39 patients evaluated Headache response: sumatriptan 74%; ⬍0.001
placebo; 2 attacks placebo 26%

August 3, 2010
7 118 AAN Class I Sumatriptan 20 mg nasal spray Headache response at 30 min 85 patients treated 2 Headache response: sumatriptan 57%; 0.002
vs placebo; 2 attacks attacks placebo 26%

8 78 AAN Class I Zolmitriptan 5 or 10 mg nasal Headache response at 30 min 52 patients treated attack Headache response: zolmitriptan 10 mg ⬍0.01; ⬍0.05
spray vs placebo; 3 attacks 63.3%; zolmitriptan 5 mg 50%; placebo 30%

9 92 AAN Class I Zolmitriptan 5 or 10 mg nasal Headache response at 30 min 69 patients treated attack Headache response: zolmitriptan 10 mg 0.002
spray vs placebo; 3 attacks 61%; zolmitriptan 5 mg 42%; placebo 23%

10 153 AAN Class I Zolmitriptan 5 or 10 mg tab vs Headache response at 30 min 124 patients took trial Headache response: zolmitriptan 10 mg 0.02
placebo; 3 attacks med,123 evaluated 47%; zolmitriptan 5 mg 40%; placebo 29%

11 19 AAN Class I 100% oxygen 6 L/min vs room Headache relief during attack All patients treated attacks Headache relief: oxygen 56%; room air 7% ⬍0.01
air; 1 attack

12 15 AAN Class II Cocaine 1 mL intranasal vs Complete cessation of pain 9 patients had nitroglycerin Complete cessation of pain: cocaine 31.3 min; ⬍0.01 No statement on allocation
lidocaine 1 mL intranasal vs induced attacks and were lidocaine 37.0 min; placebo 59.3 min concealment
placebo; 1 attack treated

13 57 AAN Class II Octreotide SC 100 ␮g vs Headache response at 30 min 48 patients treated attack Headache response: octreotide 52%; placebo ⬍0.01 No statement on allocation
placebo; 1 attack 36% concealment

14 25 AAN Class III Dihydroergotamine 1 mg nasal Reduction in headache severity 22 treated attacks Number of attacks strongly reduced: ⬍0.05 No statement on allocation
spray vs placebo; maximum 8 during the attack (not well- dihydroergotamine 41; placebo 12 concealment; no primary
attacks defined) outcome stated

15 8 AAN Class III Somatostatin 25 ␮g IV vs Reduction of maximal pain Not stated Maximal pain reduction: somatostatin 18%; ⬍0.016 No statement on allocation
ergotamine 250 ␮g IM vs intensity (not well-defined) ergotamine 14%; placebo 0% concealment; no primary
placebo IV; 1 attack outcome stated

30 19 AAN Class III Prednisone 30 mg tablet vs Pain relief (not well-defined) All patients treated attacks 17/19 patients improved ⬍0.03 No statement on allocation
placebo concealment; no primary
outcome stated

31 109 AAN Class I 100% oxygen 12 L/min vs Pain-free at 15 min 76 received treatment Pain-free at 15 minutes: 78% oxygen; 20% ⬍0.001
room air; 4 attacks air

Abbreviations: AAN ⫽ American Academy of Neurology; SC ⫽ subcutaneous.

 Table 2 Summary of results: The effect of short-term prevention on cluster headache

Reference Quality
no. No. assessment Intervention Primary outcome Dropouts Results p Value Quality criteria unfulfilled

16 28 AAN Class I Civamide 100 ␮L intranasal vs placebo; 3 wk Change in attack frequency per wk 4 did not Change in attack frequency at 1 wk 0.03
assessed complete posttreatment: civamide 55.5%;
placebo 25.9%

17 23 AAN Class I Rapid- and long-acting steroids (Verum) 2.5 mL Disappearance of attacks at All Headache-free: Verum 85%; 0.0001
vs placebo SC; 2 wk assessed 72 h–1 wk completed placebo 0%

19 96 AAN Class I Sodium valproate 500 mg tab vs placebo; 2 wk % of patient improvement (⬎50% 1 did not % patient improvement: sodium NS
assessed reduction in attacks/wk) complete valproate 50%; placebo 62%

18 168 AAN Class I Sumatriptan 100 mg tab tid vs placebo; 1 wk ⬎50% reduction in attack frequency All Reduction in attack frequency: NS
assessed completed sumatriptan 23%; placebo 22%

20 27 AAN Class II Lithium 800 mg tab vs placebo; 1 wk assessed Cessation of attacks within 1 wk All Cessation of attacks: lithium 15%; NS No statement on allocation
completed placebo 14% concealment

21 20 AAN Class II Melatonin 10 mg tab vs placebo; 2 wk Reduction in daily headache frequency All Reduction in headache frequency: ⬍0.03 No statement on allocation
assessed compared to run-in period completed melatonin ⫺1.79; placebo ⫹0.12 concealment

22 8 AAN Class II Misoprostol (prostaglandin E analogue) 300 ␮g Attack frequency 2 wk posttreatment All Attack frequency: misoprostol NS No statement on allocation
tab bid vs placebo; 2 wk assessed completed 25.1; placebo 26.1 concealment

23 16 AAN Class II 100% oxygen (hyperbaric) vs sham; 2 attacks ⬎50% reduction in headache index All Patients with ⬎50% reduction in NS No statement on allocation
following 1 wk of treatment completed headache index: hyperbaric oxygen concealment
35.7%; sham 37.5%

24 30 AAN Class II Verapamil 120 mg tab tid vs lithium 300 mg Headache index relative to placebo 6 did not Reduction in headache index: ⬍0.01 No statement on allocation
tab tid; 8 wk assessed period complete verapamil 50%; lithium 37% concealment

25 30 AAN Class III Verapamil 120 mg tab tid vs placebo; 2 wk Daily attack frequency per wk All Attack frequency: verapamil 0.6; ⬍0.001 No statement on allocation
assessed completed placebo 1.65 concealment, primary
outcome not clearly stated

26 15 AAN Class III Cimetidine 400 mg tid ⫹ chlorpheniramine 4 Mean number of attacks per wk 3 did not Mean number of attacks at wk 12: NS No statement on allocation
mg tid vs placebo; 6 wk assessed complete cimetidine ⫹ chlorpheniramine 8.7; concealment, intervention
placebo 10.7 not clearly stated

27 10 AAN Class III Cimetidine 400 mg qid vs placebo; 6 wk Headache incidence and duration 1 did not Incidence improvement: cimetidine NS No detailed results; no
assessed complete 4; placebo 0 statement on allocation

Neurology 75
concealment

28 17 AAN Class III Capsaicin intranasal cream vs placebo; 2 wk Headache severity rating over 2 wk 3 excluded Headache severity ratings: ⬍0.05 Assembly of incomparable
assessed capsaicin 2.46; placebo 5.15 groups; intervention not
clearly stated; no
statement on allocation
concealment

August 3, 2010
29 9 AAN Class III Nitrate tolerance 5-ISMN 30 mg tab tid vs Summed maximal interval headache 4 did not Median summed maximal NS No statement on allocation
placebo; 4 wk assessed score complete headache score: nitrate tolerance concealment, inadequate
42; placebo 0 accounting for dropouts

30 19 AAN Class III Prednisone 20 mg every other day for 1 wk vs Attack frequency (not defined) All Greater attack frequency in ⬍0.03 No statement on allocation
placebo completed placebo group, data not given concealment; no primary
outcome stated

Abbreviations: AAN ⫽ American Academy of Neurology; NS ⫽ not significant; SC ⫽ subcutaneous.

467
 Table 3 Summary of advisements for acute abortive treatment of cluster headache

Maneuver Effectiveness Levels of evidence Advice

Sumatriptan Direct evidence that sumatriptan 6 mg is Two randomized, controlled Level A: should be offered for
(subcutaneous) effective in improving headache clinical trials; 2 AAN Class I acute treatment of CH
response in CH. Nonserious adverse
events: injection site reactions, nausea
and vomiting, dizziness, fatigue,
paresthesias.

Zolmitriptan (nasal Direct evidence that zolmitriptan 5 mg Two randomized, controlled Level A: should be offered for
spray) and 10 mg are effective in improving clinical trials; 2 AAN Class I acute treatment of CH
headache response in CH. Nonserious
adverse events: unpleasant taste, nasal
cavity discomfort, somnolence,
dizziness, nausea, throat/neck tightness.

Sumatriptan (nasal Direct evidence that sumatriptan 20 mg One randomized, controlled Level B: should be considered
spray) is effective in improving headache clinical trial; AAN Class I for acute treatment of CH
response in CH. Nonserious adverse
event: bitter taste.

Zolmitriptan (oral) Direct evidence that zolmitriptan 5 mg One randomized, controlled Level B: should be considered
and 10 mg are effective in improving clinical trial; AAN Class I for acute treatment of CH
headache response in CH. Nonserious
adverse events: paresthesias, heaviness,
asthenia, nausea, dizziness, nonchest
tightness.

Oxygen Direct evidence that 100% oxygen 6– Two randomized, controlled Level A: should be offered for
12 L/min is effective in improving clinical trials; AAN Class I acute treatment of CH
headache response in CH. Adverse
events not reported.

Cocaine/lidocaine Evidence that 10% cocaine One randomized, controlled Level C: may be considered
hydrochloride and 10% lidocaine are clinical trial; AAN Class II for acute treatment of CH
effective in improving headache
response in CH. Nonserious adverse
events: nasal congestion, unpleasant
lidocaine taste.

Octreotide Evidence that octreotide 100 ␮g is One randomized, controlled Level C: may be considered
effective in improving headache clinical trial; AAN Class II for acute treatment of CH
response in CH. Nonserious adverse
events: injection site reactions, diarrhea,
abdominal bloating, nausea, dull
background headache, lethargy.

Dihydroergotamine Insufficient evidence that
(nasal spray) dihydroergotamine 1 mg intranasally is
effective in improving headache
response in CH. Adverse events not
reported.
One randomized, controlled Level U: insufficient evidence
clinical trial; AAN Class III to advise for the acute
treatment of CH

Somatostatin Insufficient evidence that somatostatin One randomized, controlled Level U: insufficient evidence
25 ␮g is effective in improving headache clinical trial; AAN Class III to advise for the acute
response in CH. Nonserious adverse treatment of CH
event: nausea without vomiting.

Prednisone Insufficient evidence that prednisone 30 One randomized, controlled Level U: insufficient evidence
mg is effective in improving headache clinical trial; AAN Class III to advise for the acute
response in CH. treatment of CH

Abbreviations: AAN ⫽ American Academy of Neurology; CH ⫽ cluster headache.

and 2.61 (95% CI 1.47– 4.61, p ⫽ 0.001) for zolmi-
triptan 5 mg. The most common AEs reported were
bad taste (22%), nasal cavity discomfort (12%), and
somnolence (8%).
Zolmitriptan oral, 5 and 10 mg. Headache response at
30 minutes: a single crossover study investigated
oral zolmitriptan 10 mg and 5 mg vs placebo for 3
attacks in 102 patients.10 Both doses of zolmi-
triptan doses were superior to placebo in patients
with episodic CH ( p ⬍ 0.05), but not those with
chronic CH. The most common AEs reported
were paraesthesia, heaviness, asthenia, nausea, diz-
ziness, and nonchest tightness.
Zolmitriptan NS should be offered to patients for
acute treatment of CH (Level A). Oral zolmitriptan
should be considered for acute treatment of episodic
CH (Level B).
Oxygen. Two Class I crossover studies have investi-
gated 100% oxygen vs placebo for the acute treat-
ment of CH. Fogan’s study11 evaluated 100%
oxygen vs placebo (regular air), at a rate of 6 L/min
for up to 15 minutes during an acute attack. Nine-
teen patients treated up to 6 attacks. The primary
endpoint was headache relief following treatment. A
total of 56% of patients breathing oxygen perceived
substantial headache relief, compared with 7% of
those treated with placebo ( p ⬍ 0.01). AEs were not
reported.
A more recent study by Cohen et al.31 assessed
100% oxygen at 12 L/min for 15 minutes vs regular

468 Neurology 75 August 3, 2010

air for the acute treatment of CH. Patients treated 4
attacks, 2 with each treatment, in a crossover fashion.
The primary endpoint was pain-free response at 15
minutes. Patients were pain-free at 15 minutes in
78% of attacks treated with oxygen, compared to
20% of attacks treated with air ( p ⬍ 0.001). No
serious adverse events occurred.
One hundred percent oxygen should be offered
for acute treatment of CH (Level A).
Cocaine/lidocaine. One Class II RCT assessed cocaine
intranasal vs lidocaine intranasal and placebo.12 The
study was a parallel-group design with 9 patients re-
ceiving 40 –50 mg of either10% cocaine hydrochlo-
ride, 10% lidocaine, or placebo intranasally for 1
nitroglycerin-induced headache. The primary endpoint
was the time elapsed until obtaining pain relief. On av-
erage, complete cessation of pain occurred after 31.3
minutes for cocaine, 37.0 minutes for lidocaine, and
59.3 minutes for saline (p ⬍ 0.01 for both study medi-
cations). The most common side effects were nasal con-
gestion following study medication administration as
well as unpleasant taste of lidocaine.
Intranasal cocaine and lidocaine may be consid-
ered for acute treatment of CH (Level C).
Octreotide. One Class II crossover study evaluated
subcutaneous octreotide in 57 patients for the treat-
ment of 2 CH attacks.13 The primary endpoint was
headache response at 30 minutes. A total of 52% of
patients treated with octreotide reported headache relief
in 30 minutes, compared to 36% of patients treated
with placebo (p ⫽ 0.007). Eight patients taking oct-
reotide reported diarrhea, abdominal bloating, or nau-
sea. Other AEs included a dull background headache,
lethargy, and injection-site reactions.
Octreotide may be considered for acute treatment
of CH (Level C).
Dihydroergotamine, ergotamine, somatostatin, and
prednisone. There are single Class III RCTs investigat-
ing dihydroergotamine NS,14 IM ergotamine,15 IV
somatostatin,15 and prednisone30 for the acute treat-
ment of CH. While all of these trials reported symp-
tomatic benefit, these studies had important
methodologic limitations, preventing evidence-based
advice to be given.
There is insufficient evidence to advise the use of
dihydroergotamine, ergotamine, somatostatin, and
prednisone for the acute treatment of CH (Level U).
Preventive treatment. Which preventive treatments
for CH are effective in reducing headache frequency,
duration, and pain? See table 4 for a summary of
suggestions.
Civamide. One Class I RCT investigated civamide
intranasal vs placebo16 for cluster prophylaxis. A total
of 28 patients received either 100 ␮L of 0.025% civ-
amide into each nostril daily or placebo for 7 days.
Patients were observed for 20 days posttreatment.
The primary endpoint was change in frequency of
CH attacks per week during the observation period.
For the first 7 days of observation, patients taking
civamide had a greater decrease in the number of
headaches compared to the placebo group (⫺55.5%
vs ⫺25.9%; p ⫽ 0.03) and a greater decrease for the
entire posttreatment period that approached signifi-
cance (⫺61.4% vs ⫺30.9%; p ⫽ 0.054). The most
common reported AEs were nasal burning (78%),
lacrimation (50%), pharyngitis (44%), and
rhinorrhea (33%).
Intranasal civamide should be considered for the
prevention of CH (Level B).
Suboccipital steroid injection. There is 1 Class I RCT
investigating suboccipital steroid injections vs plac-
ebo.17 The study medication consisted of 12.46 mg
betamethasone dipropionate and 5.26 mg beta-
methasone disodium phosphate mixed with 0.5 mL
Xylocaine 2%. A total of 23 patients participated in
the study. The primary endpoint was the disappear-
ance of CH attacks within 72 hours. A total of 85%
of patients in the study group had relief of attacks by
72 hours, compared to 0% of patients in the placebo
group ( p ⬍ 0.0001). Two patients reported transient
pain at the injection site.
Suboccipital steroid injection should be consid-
ered for the prevention of CH (Level B).
Sumatriptan, sodium valproate. There are single
Class I RCTs on the use of oral sumatriptan 100 mg
3 times18 daily and sodium valproate 500 mg19 vs
placebo for the prevention of CH. Neither of these
treatments resulted in a significant decrease in CH
attacks.
Sumatriptan and sodium valproate are not ad-
vised for the prevention of CH (Level B).
Lithium. There is 1 Class II RCT comparing lith-
ium 800 mg daily to placebo20 in patients with epi-
sodic CH, and one Class II RCT comparing lithium
900 mg daily to verapamil24 in patients with chronic
CH. The parallel-group study comparing lithium to
placebo assessed the percentage of patients in whom
attacks ceased within 1 week as the primary outcome.
A secondary endpoint was the percentage of patients
who were substantially better subjectively within 1
week. There was no difference in the percentage of
patients having cessation of attacks in the lithium
group (15%) compared to the placebo group (14%).
More patients, however, felt substantially better in
the lithium group (70%) than in the placebo group
(43%), though significance was not calculated. The
common AE reported by patients was polyuria.
Bussone et al.24 compared verapamil 360 mg
daily for 8 weeks to lithium 900 mg daily in a
Class II study. Thirty patients with chronic CH
Neurology 75 August 3, 2010 469
 Table 4 Summary of advisements for preventive treatment of cluster headache
Maneuver Effectiveness
Civamide Direct evidence that civamide 100 ␮L is
effective in improving headache response
in CH. Nonserious adverse events: nasal
burning, lacrimation, pharyngitis,
rhinorrhea.
Suboccipital Direct evidence that long- and rapid-acting
steroid injection steroids 2.5 mL are effective in improving
headache response in CH. Nonserious
adverse event: transient injection site pain.
Sodium valproate Direct evidence that sodium valproate 500
mg is not effective in improving headache
response in CH. Adverse events not
reported.
Sumatriptan Direct evidence that sumatriptan 100 mg
is not effective in improving headache
response in CH. Nonserious adverse
events: nausea, vomiting, headache,
malaise.
Melatonin Evidence that melatonin 10 mg is effective
in improving headache response in CH.
Nonserious adverse events: none reported.
Verapamil Evidence that verapamil 360 mg is
effective in improving headache response
in CH. Nonserious adverse events:
constipation, reduced blood pressure,
reduced heart rate.
Cimetidine/ Evidence that cimetidine 2,000 mg and
chlorpheniramine chlorpheniramine 20 mg are not effective
in improving headache response in CH.
Nonserious adverse events: transient,
erythematous skin rash. Other adverse
events not reported.
Lithium Evidence that lithium 900 mg is effective
in improving headache response in CH.
Nonserious adverse event: polyuria.
Misoprostol Evidence that misoprostol 300 ␮g is not
effective in improving headache response
in CH. Adverse events not reported.
Oxygen Evidence that 100% hyperbaric oxygen is
not effective in improving headache
response in CH. Adverse events not
reported.
Capsaicin Insufficient evidence that capsaicin is
effective in improving headache response
in CH. Adverse events not reported.
Nitrate tolerance Insufficient evidence that nitrate tolerance
via 5-ISMN 30 mg is effective in improving
headache response in CH. Adverse events
not reported.
Prednisone Insufficient evidence that prednisone 20
mg every other day is effective in
improving headache response in CH.
Adverse events not reported.
Abbreviations: AAN ⫽ American Academy of Neurology; CH ⫽ cluster headache.
participated in this crossover study, and outcomes
included the intensity, frequency, and duration of
attacks during the trial period. A total of 50% of
patients in the verapamil group and 37% of those
in the lithium group experienced an improvement
in the headache index, compared to the run-in pe-
riod ( p ⬍ 0.01).
Lithium may be considered for the prevention of
CH (Level C).
Melatonin. There is 1 Class II RCT on melatonin
for cluster prevention.21 This placebo-controlled,
parallel-group trial of 20 patients investigated mela-
470 Neurology 75 August 3, 2010
Levels of evidence Advice
One randomized, controlled Level B: should be considered
clinical trial; AAN Class I for the prevention of CH
One randomized, controlled Level B: should be considered
clinical trial; AAN Class I for the prevention of CH
One randomized, controlled Level B: not advised for the
clinical trial; AAN Class I prevention of CH
One randomized, controlled Level B: not advised for the
clinical trial; AAN Class I prevention of CH
One randomized, controlled Level C: may be considered
clinical trial; AAN Class II for the prevention of CH
Two randomized, controlled Level C: may be considered
clinical trials; 1 AAN Class II, for the prevention of CH
1 AAN Class III
Two randomized, controlled Level C: not advised for the
clinical trials; 2 AAN Class II prevention of CH
Two randomized, controlled Level C: may be considered
clinical trials; 2 AAN Class II for the prevention of CH
One randomized, controlled Level C: not advised for the
clinical trial; AAN Class II prevention of CH
One randomized, controlled Level C: not advised for the
clinical trial; AAN Class II prevention of CH
One randomized, controlled Level U: insufficient evidence
clinical trial; AAN Class III to advise for the prevention
of CH
One randomized, controlled Level U: insufficient evidence
clinical trial; AAN Class III to advise for the prevention
of CH
One randomized, controlled Level U: insufficient evidence
clinical trial; AAN Class III to advise for the prevention
of CH
tonin 10 mg daily vs placebo for 2 weeks. In compar-
ison to the run-in period, there was a reduction in
daily headache frequency in the melatonin group
( p ⬍ 0.03), but not the placebo group. Adverse
events were not reported.
Melatonin may be considered for the prevention
of CH (Level C).
Misoprostol, 100% hyperbaric oxygen. There are single
Class II RCTs evaluating misoprostol22 and 100%
hyperbaric oxygen23 for the prevention of CH. Nei-
ther treatment resulted in a significant decrease in
CH attacks.
 Misoprostol and 100% hyperbaric oxygen are not
advised for the prevention of CH (Level C).
Verapamil. There are 2 RCTs investigating the use
of verapamil as a preventive medication for CH.24,25
Bussone et al.24 compared verapamil 360 mg daily for
8 weeks to lithium 900 mg daily in an AAN Class II
study (results reported in Lithium section). Leone et
al.25 studied verapamil 360 mg daily vs placebo for 2
weeks in 30 patients in an AAN Class III study. The
primary endpoint was the reduction in attack fre-
quency per week. Verapamil was found to be supe-
rior to placebo, with patients taking verapamil
experiencing 0.6 attacks per day, compared to 1.65
per day in the placebo group ( p ⬍ 0.001). Reported
AEs included constipation, reduced blood pressure,
and reduced heart rate.
Verapamil may be considered for the prevention
of CH (Level C).
Cimetidine/chlorpheniramine. Two Class III RCTs
have investigated the effect of cimetidine, an H2 an-
tagonist, vs placebo.26,27 One of these studies addi-
tionally looked at chlorpheniramine, an H1
antagonist, vs placebo. Neither of these studies found
any benefit from the use of these treatments for the
prevention of cluster attacks.
Cimetidine and chlorpheniramine are not advised
for the prevention of CH (Level C).
Capsaicin, nitrate tolerance, prednisone. There are sin-
gle Class III RCTs on the use of capsaicin intranasal
cream,28 nitrate tolerance,29 and oral prednisone30 for
the prevention of CH. While the capsaicin study re-
ported less severe headaches in the treatment group
and the prednisone study reported more frequent at-
tacks in the placebo group, all studies had important
methodologic limitations.
There is insufficient evidence to advise the use of
intranasal capsaicin, nitrate tolerance, and pred-
nisone for the prevention of CH (Level U).
DISCUSSION The treatment of CH is largely phar-
macologic, although behavioral modification can
play a role in some patients, and surgical treatment
options are available for patients who do not respond
satisfactorily to drug treatment. Not all medications
which are used widely for CH based on clinical expe-
rience have been adequately studied using modern
clinical trial methodology. This review focused ex-
clusively on double-blind RCTs as such trials provide
the best evidence for therapeutic efficacy. Based on
the quality of published trials, verapamil receives a
Grade C rating. It is important to note, however,
that verapamil is generally considered to be the main-
stay of CH preventive therapy.32 Clinical experience
with both verapamil and lithium as preventive treat-
ments for CH is extensive. While both agents only
received Grade C ratings due to trial quality, they are
used much more routinely in clinical practice than
civamide, which, as a newer treatment, has only been
evaluated in 1 trial.
The evidence for the efficacy of lithium for the
prevention of CH is stronger for patients with
chronic CH than those with episodic CH. While
side effects reported in both trials were minimal,20,24
long-term use of lithium has been associated with
tremor, hypothyroidism, and nephrogenic diabetic
insipidus. Monitoring of serum lithium levels and
thyroid and renal function is recommended in pa-
tients on long-term therapy.33
The serotonin inhibitor methysergide has been
recommended for the prevention of CH in previous
guidelines,34 although no placebo-controlled,
double-blind studies of this treatment have been
completed. We have not advised methysergide for
several reasons in addition to the lack of controlled
studies. Methysergide is not available in the United
States, and has been associated with the development
of pulmonary and retroperitoneal fibrosis, and there-
fore treatment must be limited to 6 months.35,36 In
addition, methysergide should not be coadminis-
tered with triptans or ergots,37 and sumatriptan and
zolmitriptan are standard symptomatic treatments
for CH. We recognize that there may be special clin-
ical scenarios in which the use of methysergide may
be appropriate but believe that general endorsements
for use of this drug should be avoided.
The use of a short course of steroids to stop a
cluster bout is common and, based upon clinical ex-
perience, effective. It is recommended in previous
guidelines.34 However, aside from the trial that ex-
amined the efficacy of suboccipital steroid injec-
tion,17 only 1 Class III RCT of steroids in CH has
been performed.30
Conceptually, one can consider some of the med-
ications used in CH as transitional preventive treat-
ments. Transitional treatments are medications that
are started with longer-term preventive drugs. Their
function is to stop the CH attacks almost immedi-
ately, and to maintain this pain relief until the dose
of the longer-term preventive drug can be increased
and becomes effective.38 Most transitional therapies
have not been subjected to rigorous clinical trials, but
are commonly used in clinical practice. They include
oral steroids (prednisone 60 mg daily for 3 days, then
decreased by 10 mg every 3 days for a total of 18 days
of therapy)39 and dihydroergotamine (1 mg SC/IM
twice a day for several days).39 Ergotamine tartrate 1
or 2 mg given once daily or in divided doses has also
been used for transitional therapy.39 Suboccipital ste-
roid injections might also be considered transitional
therapy.38,39 Transitional therapies are especially ap-
Neurology 75 August 3, 2010 471
 propriate for patients who present with a high fre-
quency of attacks.
Finally, in refractory patients prophylactics are of-
ten used in combination. For example, verapamil
prophylaxis may be combined with lithium in an at-
tempt to control intractable cluster headaches32 even
though there is no evidence base for this practice.
CONCLUSION For the acute treatment of CH at-
tacks, Level A advice can be given for the use of
sumatriptan SC 6 mg, intranasal zolmitriptan 5 and
10 mg, and 100% oxygen. Level B advice can be
given for the use of intranasal sumatriptan 20 mg and
oral zolmitriptan 5 and 10 mg. Level C advice can be
given for intranasal 10% cocaine, intranasal 10% li-
docaine, and subcutaneous octreotide 100 ␮g.
For the prevention of CH attacks during a cluster
bout, Level B advice can be given for intranasal civ-
amide 100 ␮L and suboccipital steroid injection.
Level C advice can be given for melatonin 10 mg,
verapamil 360 mg, and lithium 900 mg.
Several new treatments are emerging for the pre-
vention of CH. Open-label and pilot studies have
been conducted with topiramate40 and gabapentin.41
Deep brain stimulation42-44 and occipital nerve stim-
ulation45 have also been assessed with small trials in
medically refractory patients. In the future, there
may be a greater number of evidence-based treat-
ment options for the prevention of CH.
When patients present with a new cluster bout, it is
appropriate to initiate both acute symptomatic therapy
and preventive therapy. Choosing between recom-
mended treatments should be based on headache fre-
quency, patient comorbidities, and side effects.
AUTHOR CONTRIBUTIONS
Statistical analysis was conducted by Dr. Tamara Pringsheim.
DISCLOSURE
Dr. Francis reports no disclosures. Dr. Becker has served on medical advi-
sory boards for Merck Serono, Pfizer Inc., Allergan, Inc., AGA Medical
Corporation, and Teva Pharmaceutical Industries Ltd.; has been a local PI
for clinical trials for Merck Serono, Allergan, Inc., Medtronic, Inc., and
AGA Medical Corporation; and has received speaker honoraria from
Merck Serono, AGA Medical Corporation, and Pfizer Inc. Dr. Pring-
sheim has served on a scientific advisory board for Pfizer Inc. and has
received speaker honoraria from Shire Canada, Pfizer Inc., and Teva Phar-
maceutical Industries Ltd.
Received December 29, 2009. Accepted in final form April 22, 2010.
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 Acute and preventive pharmacologic treatment of cluster headache
George J. Francis, Werner J. Becker and Tamara M. Pringsheim
Neurology 2010;75;463-473
DOI 10.1212/WNL.0b013e3181eb58c8

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