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Eur. J. Psychiat. Vol. 23, N.° 1, (53-60)2009
Keywords: Lithium; Cluster headache; Review.
Lithium treatment in cluster headache, review ofliterature
M.B. Abdel-Maksoud MBChB, MRCPsych*A. Nasr MBChB, MSc, MRCPsych**A. Abdul-Aziz MBChB, MSc***
* ST4 in Addiction Psychiatry, The WellsRoad Centre, The Wells Road, Nottingham
** Consultant Psychiatrist, Queen ElizabethPsychiatric Hospital, Birmingham
*** Senior House Officer, Queen ElizabethPsychiatric Hospital, Birmingham
UNITED KINGDOM
ABSTRACT – Background: The pain, which is involved in Cluster Headache (CH), is ex-cruciating and is probably one of the most painful conditions known to humans. In the early70es it was found out that lithium could be used in treating this rare condition. Ekbom pro-duced his first report of using lithium successfully to treat five cases of CH and this was fol-lowed later by other studies, which showed the effectiveness of lithium in this condition.
Objective: In this article we reviewed the evidence for using lithium in CH. We discusssome issues including the duration, the dosage of lithium required and the short and long-term side effects, which are likely to occur. We also included the mechanism of action oflithium in treating this condition.
Methodology: We searched the Medline database from 1950 to date. We included allstudies done in English, which were related to the use of lithium in cluster headache. Weexcluded all studies which were not in English and which included other types of headache.
Results and conclusions: We concluded that lithium is effective in both chronic andepisodic forms of cluster Headache.
Received 9 January 2008Revised 2 December 2008Accepted 11 December 2008
54 M.B. ABDEL-MAKSOUD ET AL.
Introduction
CH is a rare condition, which is charac-terized by severe explosive pain, which lastsfor less than three hours and occurs mainlyin males. There are two forms of CH name-ly the chronic and the episodic forms. In thechronic form, the attacks occur for morethan one year without remission or with re-mission lasting less than 1 month. In theepisodic form, the attacks occur in periodslasting 7 days to 1 year separated by painfree periods lasting 1 month or longer. Thepain is strictly unilateral in the orbital,supra-orbital, and or temporal region andassociated with ipsilateral cranial autonom-ic symptoms and signs such as conjunctivalinjection, lacrimation, nasal congestion, rhi-norrhea, miosis, and low grade ptosis. Mostpatients are restless or agitated during an at-tack1. Cluster Headache has been shown tobe associated with dysfunction in the ner-vous system, notably with involvement ofthe hypothalamus. Attacks occur with re-markable regularity and are related to REMsleep. They are followed by refractorinessfor few hours and tend to have a seasonalpattern2.
Graham suggested that the effect of lithi-um on cluster headache may be, becausethis disorder shares several characteristicswith manic depressive disease3.
Studies
Karl Ekbom did the first study when hetreated 5 patients with CH (3 with chronicCH and 2 with episodic CH). Serum lithiumlevel was maintained between 0.7& 1.2 mEq/l. Lithium was found to be effective inall 5 patients2.
In another study by Bussone et al., 20 pa-tients with a diagnosis of chronic CH weretreated with lithium carbonate. The doses oflithium varied from 900mg to 2.2 gm/day.All patients improved rapidly on treatmentand once treatment was stopped in some pa-tients the headache returned within 36hours4.
Later on, Kudrow treated a group of 32patients suffering from chronic CH withlithium carbonate. The patients had previ-ously tried different medications includingmethysergide, prednisone, and ergotaminewithout any result. Serum lithium levelswere maintained lower than 1.2 mEq/l. 27patients showed a dramatic improvement,whereas the therapy was found to be inef-fective in 5 patients5.
Mathew undertook another clinical trialof lithium carbonate on 31 patients with CH(14 episodic, and 17 chronic). 80% of thepatients responded to lithium and only 20%showed no improvement. Effectiveness oflithium was evident in less than a week afterthe initiation of treatment in those who re-sponded. 55% of patients showed mild sideeffects. Treatment was stopped in one pa-tient only because of intolerable side ef-fects6.
In a study by Peatfield, 31 patients withCH were given lithium carbonate and theserum lithium levels were maintained at0.6-0.69mmol/l. 14 patients showed amarked improvement in the first week, and10 patients showed a lesser improvement7.
Ekbom gave a further contribution in1981 when he conducted a study on 19 pa-tients (8 with chronic CH and 11 withepisodic CH). He tried lithium sulphate andlithium levels were maintained between 0.7and 1.2 mmol/l. Immediate partial remis-sion occurred in all chronic cases. In 4 caseswith episodic CH lithium was continued for
several months which resulted in completesuppression of cluster periods. The rest ofthe patients with episodic CH had slight orno benefit8.
In a trial by Faustino Savoldi et al., theyincluded 90 CH patients (68 with episodic&22 with chronic symptoms). In the 2nd weekof lithium treatment over 80% of the pa-tients with chronic CH improved by morethan 90%. In the short term, some side ef-fects occurred which were mild and tolera-ble. The doses of lithium varied from 600 to1200 mg/day and plasma lithium levels var-ied from 0.3 to 0.8 m Eq/l. Of the 68 pa-tients with episodic CH, about 3/4 improvedby > 60%. Mild side effects appeared in 18cases (tremors, thirst, and insomnia). Theplasma level varied from 0.3 to 0.7 m Eq/l9.
Manzoni et al. have investigated the shortand long-term effects of administration oflithium carbonate (900 mg/day) in 90 pa-tients with CH (68 episodic and 22 chronic).50% of the patients with chronic CH (11 pa-tients) showed a definite improvement,whereas, 50% had initial or partial improve-ment only. In 9 cases, cessation of lithiumresulted in reappearance of symptoms. Inthe episodic group, 26 patients respondedhighly, 26 patients responded partially, and16 cases were refractory. Reversible goitredeveloped in 3 cases after 1-3 years of treat-ment10.
A double blind study by Bussone et al.compared the effect of Lithium and Vera-pamil in treating CH Showed that bothLithium and verapamil are effective in pre-venting Chronic CH. They involved 30 pa-tients diagnosed with Chronic CH accord-ing to the International Headache Societycriteria11. Regarding efficacy, both drugssignificantly improved Headache Index(HI), and Analgesic Consumption (AC). Ve-rapamil showed > 50% reduction in HI and
58% in AC & Lithium showed > 37% and58% respectively in the 1st week. RegardingSide effects, both drugs showed minor sideeffects (12% for verapamil and 29% forlithium)12.
Steiner et al. conducted a double blind,placebo-controlled comparison of matchedparallel groups of patients with episodic CHwhere treatment was slow release lithiumcarbonate, 800 mg/day, or placebo. Substan-tial improvement occurred in 8/13(62% NS)on lithium and 6/14 (43%) on placebo andthe trial was stopped because superiority oflithium could not be demonstrated13.
There are other case reports whichshowed the effectiveness of lithium carbon-ate in treating both forms of CH. Wyant &Ashenhurst reported five cases of patientswho had a diagnosis of CH(4 chronic and 1episodic). They tried lithium carbonate andlater on added amitriptyline for patientswith chronic CH and lithium carbonate onlyfor the patient with episodic CH. Completeremission occurred in the patient withepisodic CH and 1 patient with chronic CH.A significant improvement occurred in 3 pa-tients with chronic CH14.
In 1978, Lieb & Zeff reported two caseswith severe chronic CH to the extent thatthey had suicidal ideations. Both cases re-sponded dramatically to lithium carbonatewith serum levels of 0.76 - 1.15 mEq/l15.
Kilmek et al. used lithium carbonate totreat 15 patients with CH (8 chronic and 7episodic). In all cases lithium serum levelwas maintained at 0.6-1.2 mmol/l. Disap-pearance of symptoms occurred in 5 pa-tients (1 chronic and 4 episodic) and signifi-cant improvement occurred in 5 patients (4chronic and 1 episodic). The treatment wasineffective in 5 patients (3 chronic and 2episodic)16.
LITHIUM TREATMENT IN CLUSTER HEADACHE, REVIEW OF LITERATURE 55
In an open trial, Damasio & Lyon triedlithium carbonate on 21 patients with CH (9episodic, 12 chronic). 52.4% (n = 11) of pa-tients showed absolute improvement, 23.8%(n = 5) showed partial improvement, and23.8% (n = 5) did not improve or had tempo-rary improvement only. Two patients had todiscontinue treatment due to side effects17.
J M S Pearce reported 3 cases of episodicCH which responded dramatically to lithiumcarbonate at a dose of 250mg tds. No side ef-fects were observed from lithium use18.
In 1980, Manzoni and Terzano tried lithiumcarbonate at gradually increased doses in 6patients with chronic CH. The effective doseof lithium varied from 300 to 900mg/day19.
Zuddas et al. reported a case of chronic CHon haemodialysis treatment where lithiumwas used and led to a complete recovery20.
Mechanism of action oflithium
Some trials have been undertaken in anattempt to understand how lithium works inpatients with Cluster Headache.
Kupfer et al.21 and Mendels & Chernik22
reported that the immediate action of lithi-um in treating CH is related to its effect onREM sleep.
In another study by Medina et al., it wasfound that lithium effect on CH is related toits effect on platelet serotonin and histaminelevels23.
It was also suggested that lithium actionin CH can be attributed to its effect on opi-ate receptor affinity24.
Giacovazzo et al. studied the relationshipbetween genetic markers of patients with
CH and the therapeutic efficacy of lithium.In this study, 35 patients with episodic CHwere involved. Lithium level was kept be-tween 0.7 and 1.2 mEq/l. Two subgroupswere identified (responders n = 21 and nonresponders n = 14). Responders displayed ahigher frequency of the antigens HLA-B18and HLA-A9 than did the non responders.The latter, on the other hand, showed a high-er frequency of HLA-A1 than did the re-sponders25.
It was also found that lithium can correctthe bilateral neuronal asymmetries whichare related to the pathogenesis of CH26.
In a study by De Bellaroche et al., it wasfound that lithium restored the erythrocytecholine concentrations which were marked-ly reduced in patients with CH. This findingwas consistent with a subsequent studywhich showed a decreased turnover in theerythrocyte phosphatidylcholine in CH suf-ferers27,28.
Winter et al. suggested that the mecha-nism of action of lithium in CH lies behindits antiviral actions29. This was based on thetheory which suggests an association be-tween CH and herpes simplex30.
A study by G Chazot et al. showed thechronobiological effect of lithium in clusterheadache. The result showed a decrease inmelatonin amplitude at day 0 in the clustergroup together with a rise in the cortisol.However in day 7 there was a delay in mela-tonin secretion with a shift but clear in-crease of the acrophase was observed. A de-crease in cortisol level was also observed31.
The cyclic nature and hormonal alter-ations in CH indicate the involvement of thehypothalamus in the pathogenesis of thisdisorder. One possible mechanism of actionof lithium is its effect on the serotonin levelin the hypothalamus32.
56 M.B. ABDEL-MAKSOUD ET AL.
LITHIUM TREATMENT IN CLUSTER HEADACHE, REVIEW OF LITERATURE 57Ta
ble
ISu
mm
ary
of s
tudi
es o
f us
ing
lithi
um in
Clu
ster
Hea
cach
e
Stud
yN
o.C
hron
icE
piso
dic
Lith
ium
Dos
age
Res
ults
Side
eff
ects
Of
pts
CH
CH
and/
or L
evel
Ekb
om2
53
20.
7-1.
2 m
Eq/
l10
0% im
prov
edN
il re
port
ed
Kud
row
532
320
<1.
2 m
Eq/
l27
pat
ient
s im
prov
ed d
ram
atic
ally
.4
patie
nts
disc
ontin
ued
beca
use
of s
ever
e si
de e
ffec
ts
5 pa
tient
s di
d no
t res
pond
.(h
eada
che,
abdo
min
al p
ain,
and
vom
iting
).
Mat
hew
631
1714
Up
to 9
00m
g/d
80%
sho
wed
impr
ovem
ent (
>90
%i
55%
of
patie
nts
show
ed m
ild s
ide
effe
cts
(tre
mor
s,L
evel
:0.5
-1.2
mE
q/l
impr
ovem
ent i
n 55
%,6
0-90
%
naus
ea,d
iarr
hea,
and
abdo
min
al d
isco
mfo
rt).
im
prov
emen
t in1
0%,2
5-60
%
1 pa
tient
dis
cont
inue
d du
e to
into
lera
ble
side
eff
ects
im
prov
emen
t in
15%
).(d
isab
ling
leth
argy
).20
% s
how
ed n
o im
prov
emen
t
Peat
fiel
d731
427
800-
1600
mg
noct
eM
arke
d im
prov
emen
t- 1
4 pa
tient
s.In
trac
tabl
e vo
miti
ng in
duce
d in
2 c
ases
.L
evel
:0.6
0-0.
69
Les
ser
impr
ovem
ent-
10 p
atie
nts.
mm
ol/l
No
impr
ovem
ent-
7 pa
tient
s.
Ekb
om8
198
110.
7-1.
2mm
ol/l
8 C
hron
ic c
ases
sho
wed
imm
edia
te
3 pa
tient
s in
the
chro
nic
grou
p re
port
ed s
light
pa
rtia
l rem
issi
on.
diar
rhea
,tre
mor
,and
incr
ease
d th
irst
.7
epis
odic
pat
ient
s sh
owed
slig
ht o
r 3
patie
nts
in th
e ep
isod
ic g
roup
rep
orte
d tir
edne
ss,
no e
ffec
t.tr
emor
,ver
tigo,
diar
rhea
,and
incr
ease
d th
irst
.4
epis
odic
cas
es s
how
ed c
ompl
ete
rem
issi
on w
ith lo
ng te
rm tr
eatm
ent
Savo
ldi9
9022
6860
0-12
00M
ore
than
80%
of
chro
nic
case
sM
ild to
lera
ble
side
eff
ects
in 1
8 ep
isod
ic c
ases
L
evel
s:im
prov
ed>
90%
.(t
rem
ors,
thir
st,a
nd in
som
nia)
.0.
3-0.
8mE
q/l.
75%
of e
piso
dic
case
s im
prov
ed >
60%
.M
ild to
lera
ble
side
eff
ect i
n 7
chro
nic
case
s (t
rem
or,
diar
rhea
,abd
omin
al p
ain,
olfa
ctor
y ha
lluci
natio
ns,
inso
mni
a,ve
rtig
o,an
d in
crea
sed
thir
st).
Lon
g te
rm s
ide
effe
cts
incl
uded
rev
ersi
ble
goitr
e.
Man
zoni
9022
6890
0mg/
dC
onst
ant i
mpr
ovem
ent i
n 11
chr
onic
M
ild s
ide
effe
cts
(tre
mor
,inc
reas
ed th
irst
,ins
omni
a,et
al.10
case
s.di
arrh
ea,l
etha
rgy,
diff
use
head
ache
,abd
omin
al p
ain,
Hig
h re
spon
se in
26
epis
odic
cas
es.
olfa
ctor
y ha
lluci
natio
n,an
d ve
rtig
o).
3 ca
ses
deve
lope
d eu
thyr
oid
goitr
e af
ter
1-3
year
s of
tr
eatm
ent w
hich
dis
appe
ared
aft
er s
topp
ing
lithi
um.
Bus
sone
1230
300
900m
g/d
>37
% r
educ
tion
in H
I an
d 58
%
29%
of
patie
nts
deve
lope
d m
inor
sid
e ef
fect
sre
duct
ion
in A
C(g
astr
oint
estin
al c
ompl
aint
s,be
havi
oura
l cha
nges
,tr
emor
,and
incr
ease
d di
ures
is).
58 M.B. ABDEL-MAKSOUD ET AL.Ta
ble
I (c
ontin
ue)
Stud
yN
o.C
hron
icE
piso
dic
Lith
ium
Dos
age
Res
ults
Side
eff
ects
Of
pts
CH
CH
and/
or L
evel
Stei
ner13
130
1380
0mg/
d62
%;N
S 8
case
s) s
how
ed s
ubst
antia
lO
nly
min
or s
ide
effe
cts
repo
rted
(po
lyur
ea r
epor
ted
0.5-
0.6m
mol
/lim
prov
emen
tin
5 c
ases
).
Wya
nt e
t al.14
54
160
0mg/
d in
1 c
ase.
Com
plet
e re
mis
sion
in 2
cas
es
Nil
repo
rted
.L
evel
s:1.
14 a
nd
(1ep
isod
ic a
nd 1
chr
onic
).1.
28 in
2 c
ases
.Si
gnif
ican
t im
prov
emen
t in
3 ca
ses.
Lie
b &
2
20
Dos
es:1
200&
Bot
h ca
ses
impr
oved
dra
mat
ical
ly.
Mild
neu
rom
uscu
lar
side
eff
ects
in 1
cas
e.Z
eff15
1500
mg/
d.L
evel
s:0.
76-
1.15
mE
q/l
Kilm
ek e
t al.16
158
7D
oses
:750
-150
0R
emis
sion
in 5
cas
es (
1 ch
roni
c an
d 1
patie
nt d
evel
oped
into
lera
ble
side
eff
ects
and
m
g/d.
4 ep
isod
ic).
trea
tmen
t was
dis
cont
inue
d.L
evel
s:0.
6-1.
2Si
gnif
ican
t im
prov
emen
t in
5 pa
tient
sN
o ot
her
side
eff
ects
rep
orte
d.m
mol
/l(4
chr
onic
&1
epis
odic
)N
o im
prov
emen
t in
5 ca
ses
(3 c
hron
ic&
2 ep
isod
ic).
Bus
sone
20
200
900m
g-2.
2gm
/d16
cas
es im
prov
ed r
apid
ly w
ith n
o 1
patie
nt r
epor
ted
gast
ric
dist
urba
nces
and
hea
dach
eet
al.4
furt
her
cris
is w
hile
on
trea
tmen
t w
hile
on
a hi
gh d
ose.
for
2-24
wee
ks.
4 ca
ses
impr
oved
but
not
com
plet
ely.
Dam
asio
&
2112
9D
oses
:600
-150
0A
bsol
ute
impr
ovem
ent.-
11 p
atie
nts.
No
seri
ous
side
eff
ects
wer
e no
ted
but2
pat
ient
s ha
dLy
on17
mg/
day.
Part
ial i
mpr
ovem
ent-
5 pa
tient
s.
to d
isco
ntin
ue tr
eatm
ent d
ue to
sid
e ef
fect
s L
evel
:0.3
8-1.
14N
o im
prov
emen
t-5
patie
nts.
(d
iarr
hea,
poly
urea
,pol
ydyp
sia,
dizz
ines
s,an
d m
g/m
lun
stea
dine
ss).
Pear
ce18
30
325
0mg
tds
All
patie
nts
resp
onde
d dr
amat
ical
lyN
il re
port
ed.
Man
zoni
&
66
030
0mg/
d in
1 c
ase.
90%
impr
ovem
ent i
n al
l cas
es.
Nil
repo
rted
.Te
rzan
o1960
0mg/
d in
3 c
ases
.90
0mg/
d in
2 c
ases
Zud
das
et a
l.201
10
300m
g/d
duri
ng .
Com
plet
e re
cove
ry w
hen
lithi
um
Nil
repo
rted
.di
alys
isle
vel r
each
ed 0
.46
mm
ol/l.
150m
g/d
duri
ng
non
dial
ysis
.
LITHIUM TREATMENT IN CLUSTER HEADACHE, REVIEW OF LITERATURE 59
Discussion
We concluded from our review that lithi-um can be effective in both types of clusterheadache but, perhaps, the evidence of itseffectiveness in episodic forms is rathercontroversial. Some authors found thatthere is a decrease in the effectiveness oflithium after prolonged use in this condi-tion. This may be due to tolerance or lackof compliance for one reason or another.There is a controversy regarding the re-quired dose of lithium in patients with CHand some authors required higher doses toreach a plasma level between 0.7-1.2mmol/l. Others, on the other hand, foundthat low doses of lithium with plasma levelsbetween 0.4-1.0 mmol/l should be adequatefor this condition.
In the short term the side effects of lithi-um are generally tolerable and they aremainly in the form of fine hand tremors,polyurea, and polydypsia. In the long term,hypothyroid goitre and renal impairmentmay develop. Hypothyroidism secondary tolong-term lithium treatment can be treatedand should not be an indication to stop lithi-um in stable clients. It is important that pa-tients be well informed as to the needs forperiodic lithium blood level determinationsand the adverse as well as the beneficial ef-fects of the drug.
It should be noted that with exception ofthe two studies done by Bussone et al.12,and Steiner et al.13, results have been de-rived solely from open clinical trials.
Although there are different theories be-hind the mechanism of action of lithium intreating CH, however, it remains unclear tohow exactly it works and produces its rapideffect in this condition.
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60 M.B. ABDEL-MAKSOUD ET AL.
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Address for correspondence:Dr. M B Abdel-Maksoud ST4 in Addiction Psychiatry,The Wells Road Centre,The Wells Road,Nottingham,NG3 3AA.U.K.Tel.: 01159691300 ext.:11122Fax: 01159529422 E-mail: [email protected]
