Memantine as an Add-on Therapy in Alcohol Withdrawal Syndrome

Abstract

Memantine as an add-on therapy in alcohol withdrawal syndrome Objective: NMDA receptor antagonists were found to be effective treating alcohol withdrawal syndrome, preventing seizures, and decreasing daily alcohol intake in preclinical studies. But there were only few studies on the efficacy of NMDA receptor antagonists in humans. In this current study, we evaluated the effects of memantine, an NMDA receptor antagonist on alcohol withdrawal syndrome. Methods: The study was planned as a prospective, randomized; double-blind study. In total, 32 patients enrolled in study. 16 patients were randomized to benzodiazepine plus memantine group and 16 were randomized to benzodiazepine plus placebo group. Memantine was administered to patients as 10 mg/day in first week of study and 20 mg/day in second week of study. Severity of alcohol withdrawal was measured by Revised Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-AR). Mean Corpuscular Volume (MCV), Gama Glutamyl transferase (GGT), Carbohydrate Deficient Transferrine (CDT), and Alcohol Using Disorders Identity Test (AUDIT) tests were also administered to evaluate patients. CIWA-AR scores of the two groups were compared with Mann-Whitney U test at 1 st

Full text

359
Klinik Psikofarmakoloji Bülteni, Cilt: 19, Say›: 4, 2009 /
Bulletin of Clinical Psychopharmacology, Vol: 19, N.: 4, 2009 -
www.psikofarmakoloji.org
Memantine as an Add-on Therapy in
Alcohol Withdrawal Syndrome
Cem Sengul1, Ceyhan Balci Sengul2, Tuncer Okay3, Nesrin Dilbaz3
ÖZET:
Alkol geri çekilme sendromunda ek tedavi ola-
rak memantinin etkinli¤i
Amaç: NMDA reseptör antagonistlerinin alkol geri çekilme
sendromunun tedavisinde, nöbetleri önlemede ve günlük
al›nan alkol miktar›n› azaltmada etkili oldu¤u yap›lan prek-
linik çal›flmalarda gösterilmifltir. Ancak insanlarda alkol yok-
sunlu¤u sendromunda NMDA reseptör antagonistlerinin
etkinli¤i ile ilgili çok az say›da çal›flma vard›r. Bu çal›flmada
bir NMDA reseptör antagonisti olan memantinin alkol geri
çekilme sendromu tedavisinde etkinli¤ini ölçmeyi amaçla-
d›k.
Metot: Çal›flma prospektif, randomize, çift kör bir çal›flma
olarak planlanm›flt›r. Çal›flmaya toplam 32 hasta al›nd›. 16
hasta benzodiazepin ve memantin grubuna randomize
edilirken, 16 hasta benzodiazepin ve plasebo grubuna ran-
domize edildi. Hastalara ilk hafta 10mg/gün memantin ve-
rilirken, ikinci hafta doz 20 mg/gün memantine yükseltildi.
Alkol geri çekilme belirtilerinin fliddeti Gözden Geçirilmifl
Alkol Geri Çekilme fiiddeti Derecelendirme Formu
(CIWA-AR) ile ölçüldü. Hastalar› de¤erlendirmek için ayr›ca
Alkol Kullan›m Bozukluklar› Tarama Testi (AKBTT), Karbon-
hidrattan yoksun transferin (CDT), ortalama eritrosit hacmi
(MCV) ve gama glutamil transferraz (GGT) testleri kullan›ld›.
Mann-Whitney-U testi kullan›larak1., 4., 7., 10. ve 15. gün-
lerde iki grubun CIWA-AR skorlar› karfl›laflt›r›ld›. Çoklu test-
ler için p de¤erleri düzeltildi.
Bulgular: Her iki grupta yafl, cinsiyet, evlilik hali, e¤itim ve
ifl sahibi olma aç›s›ndan benzer özellikler gösteriyordu. Ay-
r›ca çal›flman›n bafllang›c›nda her iki grup aras›nda AUDIT,
CDT, MCV ve GGT skorlar› aç›s›ndan fark bulunmad›. Çal›fl-
man›n bafllang›c›nda memantin grubunun CIWA-AR skoru
ortalamas› 23.63±7.24 iken plasebo grubunun CIWA-AR
skoru ortalamas› 22.94±7.47 olarak tespit edildi. Gruplar
aras›ndaki fark istatistiksel olarak anlaml› de¤ildi. 4., 7, 10.
ve 15. ölçüm günlerinde memantin kullanan hastalar›n
CIWA-AR skorlar› s›ras›yla 7.88±4,37, 2.44±2.03, 0.94±0.99
ve 0.25±0.44’dü. Plasebo grubundaki hastalar›n 4., 7, 10. ve
15. ölçüm günlerindeki CIWA-AR skorlar› ise s›ras›yla
8.63±4,79, 4.19±2.10, 2.50±1.82 ve 1.13±0.96 bulundu. Ek
ilaç olarak memantin kullananlarda CIWA-AR skorlar›nda
düzelme daha iyi olmas›na karfl›n, aradaki fark istatistiksel
olarak anlaml› de¤ildi. Memantin kullananlarda ayr›ca
CIWA-AR ölçe¤inin tremor ve terleme gibi alt ölçek puanla-
r›nda daha fazla düflüfl bulundu. Yine de iki grup aras›nda-
ki fark istatistiksel olarak anlaml› de¤ildi.
Sonuç: Memantinin alkol geri çekilme sendromu tedavisin-
de etkili oldu¤unu gösteren çal›flmalara karfl›n çal›flmam›z-
da istatistiksel olarak anlaml› bir farkl›l›k bulmad›k. Bizim
çal›flmam›zda memantinin plaseboya üstünlü¤ü yoktu. Bu-
na ra¤men daha fazla denek say›s›yla, ek ilaç verilmeden
yap›lacak randomize plasebo kontrollü çal›flmalar, meman-
tinin ve di¤er antiglutamaterjik ajanlar›n alkol geri çekilme
sendromundaki etkinli¤ini göstermede yard›mc› olabilir.
Anahtar sözcükler: Memantin, NMDA, alkol geri çekilmesi
Klinik Psikofarmakoloji Bülteni 2009;19:359-364
ABSTRACT:
Memantine as an add-on therapy in alcohol
withdrawal syndrome
Objective: NMDA receptor antagonists were found to be
effective treating alcohol withdrawal syndrome, preventing
seizures, and decreasing daily alcohol intake in preclinical
studies. But there were only few studies on the efficacy of
NMDA receptor antagonists in humans. In this current
study, we evaluated the effects of memantine, an NMDA
receptor antagonist on alcohol withdrawal syndrome.
Methods: The study was planned as a prospective,
randomized; double-blind study. In total, 32 patients enrolled
in study. 16 patients were randomized to benzodiazepine
plus memantine group and 16 were randomized to
benzodiazepine plus placebo group. Memantine was
administered to patients as 10 mg/day in first week of study
and 20 mg/day in second week of study. Severity of alcohol
withdrawal was measured by Revised Clinical Institute
Withdrawal Assessment for Alcohol scale (CIWA-AR). Mean
Corpuscular Volume (MCV), Gama Glutamyl transferase
(GGT), Carbohydrate Deficient Transferrine (CDT), and
Alcohol Using Disorders Identity Test (AUDIT) tests were also
administered to evaluate patients. CIWA-AR scores of the two
groups were compared with Mann-Whitney U test at 1
st
, 4
th
,
7
th
, 10
th
, and 15
th
days of treatment. P values were corrected
for multiple comparisons.
Results: Two groups were identical on age, sex, marital
status, education and employment. There were also no
differences in AUDIT, CDT, MCV, and GGT scores between
two groups at the beginning of the study. Mean CIWA-AR
score of the memantine group was 23.63±7.24 and mean
CIWA-AR score of the placebo group was 22.94±7.47 at the
beginning of the study. The difference between two
groups was not statistically significant. CIWA-AR scores of
the memantine group were 7.88±4,37, 2.44±2.03,
0.94±0.99, and 0.25±0.44 respectively on the 4
th
, 7
th
, 10
th
and 15
th
measurement days. CIWA-AR scores of the
placebo group were 8.63±4,79, 4.19±2.10, 2.50±1.82, and
1.13±0.96 respectively on the 4
th
, 7
th
, 10
th
and 15
th
measurement days. Although the decline in CIWA-AR
scores was higher in memantine group, there was no
statistically significant difference between memantine and
placebo group. Memantine group had better
improvement in tremor and sweating subscales of CIWA-
AR but this difference was not statistically significant.
Discussion: Despite the previous results that were
mentioning that memantine was effective in alcohol
withdrawal syndrome, we could not find statistically
significant difference between two groups. Although
memantine was not superior to placebo in our setting,
randomized placebo controlled studies with more subjects
and no extra medication might be helpful for showing
efficacy of memantine and other antiglutamatergic agents
in alcohol withdrawal syndrome.
Key words: Memantine, NMDA, alcohol withdrawal
Bulletin of Clinical Psychopharmacology 2009;19:359-364
1Pamukkale Üniversitesi Psikiyatri AD,
Denizli-Turkey
2Denizli Devlet Hastanesi Psikiyatri Klini¤i,
Denizli-Turkey
3Ankara Numune Hastanesi, II. Psikiyatri
Klini¤i, Ankara-Turkey
Yaz›flma Adresi
/ Address reprint requests to:
Dr. Cem fiengül, Pamukkale Üniversitesi T›p
Fakültesi, Psikiyatri AD, Doktorlar Caddesi,
No: 42 Denizli, Turkey
Telefon
/ Phone
: +90-258-241-0034/144
Elektronik posta adresi
/ E-mail address:
acemsen@yahoo.com
Kabul tarihi
/ Date of acceptance:
5 May›s 2009 / May 5, 2009
Ba¤›nt› beyan›:
C.fi., C.B.fi., T.O.: yok.
N.D.: Çok say›da ilaç firmas›ndan bilimsel
aktiviteleri kar›fl›l›¤› honorarium kabul
etmifltir.
Declaration of interest:
C.fi., C.B.fi., T.O.: none.
N.D.: Received honoraria for scientific
activities from various pharmaceutical
companies.
Araflt›rmalar / Original Papers

INTRODUCTION
Alcohol acts in the brain by influencing several
different systems such as dopaminergic, serotonergic, and
glutamatergic systems (1). NMDA (N-methyl-d-aspartate)
and glutamatergic systems have been the most frequently
addressed pathways for alcohol dependency in recent
years (2). Accumulating evidence suggests that prolonged
ethanol exposure leads to a compensatory "upregulation"
of NMDA mediated functions supposedly contributing to
the occurrence of ethanol tolerance, dependence, as well
as the acute and delayed signs of ethanol withdrawal (3).
Most of the data revealing the role of glutamatergic
system in alcohol addiction comes from experimental
studies. Demonstration of efficacy of antiglutamatergic
agents in animal studies has reinforced beliefs concerning
a causative relationship between dependency and the
glutamatergic system (4). The strongest evidence for the
involvement of this system in humans as well, comes
from acamprosate clinical trials. Being a homocystic acid
derivative, acamprosate is a structural analog of
glutamate. The ability of drugs acting on NMDA
receptors, such as acamprosate and topiramate, to reduce
both withdrawal and craving behavior have drawn
attention to NMDA and glutamatergic system (5,6).
Memantine is an NMDA receptor antagonist that has
been approved for the treatment of Alzheimer’s disease. It
was synthesized in Lundbeck laboratories with the
chemical name of 1-amino-3,5-dimethyladamantane
hydrochloride. The NMDA receptor blocking effect of the
agent was discovered in late 1980s (7,8). After
demonstration of the roles of glutamate and NMDA
receptors in the course of alcohol dependency, the
molecule was initially tested in preclinical trials and then
was used in a limited number of clinical trials. Lukoyanov
et al. administered diclozipine, a non-selective NMDA
antagonist, and memantine, a selective NMDA antagonist,
to alcohol dependent mice after initiation of withdrawal
symptoms and observed that although withdrawal
symptoms did not respond to diclozapine, they were
completely abolished by memantine (9). Kotlinska
showed that memantine prevents the development of
alcohol dependency in mice (10). Memantine was also as
effective as diazepam in preventing withdrawal seizures
in alcohol dependent mice (11,12). In their study on
hypocampal cell cultures, Maler et al. have reported that
NR1, NR2A, and NR2B subunits of NMDA receptors
were induced by ethanol, however, this induction was not
observed when memantine was co-administered with
ethanol (13). Preclinical trials were suggesting that
memantine reduces withdrawal symptoms resulting from
hyperexcitability by inhibiting the stimulatory effects of
alcohol on the NMDA receptor (11,13).
Efficacy of memantine humans was tested only in few
studies. Bisaga and Evans administered 15 to 30 mg/day
of memantine to 18 volunteers and found that memantine
reduced craving if administered before alcohol intake
(14). Later, when Evans et al. conducted a study in a
double blind placebo-controlled design, memantine was
not found to be significantly more effective than placebo
in reducing alcohol intake (15). On the other hand,
Krupitsky et al. showed that memantine reduced alcohol-
related craving in a dose dependent manner (16).
In this current study, we investigated the effects of
memantine, an NMDA antagonist, administered as an
adjunctive medication in alcohol withdrawal syndrome.
MATERIALS AND METHOD
Study Design and Instruments. This study was
conducted in the Alcohol and Substance Abuse Center of
Ankara Numune Hospital and was approved by the local
Institutional Ethics Committee. Randomly selected 16
male patients between 18 and 65 years of age, who had a
diagnosis of alcohol dependency according to DSM-IV
criteria, were included in the study. An additional 16 male
patients were included as the comparison group. All
participants provided written informed consent. Those
patients with comorbid chronic medical disorders such as
diabetes mellitus, hepatic cirrhosis, anemia, hypertension
etc. were excluded from the study. All patients were
evaluated with SCID-I (Structured clinical Interview for
DSM-IV) and patients with any axis I disorder other than
nicotine dependency were also excluded from the study.
This study was designed as a prospective, randomized,
double-blind, placebo-controlled trial. Patients were
assessed for inclusion criteria on their first day of
hospitalization. In addition to a semi-structured
questionnaire form developed by the investigators
consisting of items including sociodemographic data and
detailed history of alcohol use, Alcohol Using Disorders
Identity Test (AUDIT) and Revised Clinical Institute
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Memantine as an add-on therapy in alcohol withdrawal syndrome

Withdrawal Assessment for Alcohol scale (CIWA-AR)
questionnaires were administered to each patient. AUDIT
is a 10-item screening test providing information about
drinking habits, alcohol consumption, and alcohol-related
problems (17). Validity and reliability of Turkish form of
AUDIT was made by Saatcioglu et al (18). CIWA-AR is
a 10-item scale developed by Sullivan in 1989 to measure
the severity of alcohol withdrawal syndrome (19). These
10 items are nausea, tremor, paroxysmal sweating,
anxiety, agitation, tactile disturbances, auditory
disturbances, visual disturbances, headache and
orientation. A score of < 8 is defined as mild, 9 to 14 as
moderate, and > 15 as severe withdrawal syndrome (19).
Routine investigations including a total blood count,
serum biochemistry, hepatitis markers, thyroid markers,
chest x-ray, and urinalysis were performed in all patients.
Moreover, objective biological markers that are used in
alcohol using disorders such as gamma glutamyl
transferase (GGT), mean corpuscular volume (MCV) and
carbohydrate deficient transferrin (CDT) were measured.
For serum CDT level measurement, blood samples of all
patients were obtained from their antecubital veins into
anticoagulant-free test tubes at admission (prior to
detoxification therapy was initiated). Serum samples were
stored at -70°C after being centrifuged at 4000 rpm for 10
min. CDT% was assessed by Turbidimetric Immunoassay
(TIA) method using Bio-Rad CDT% TIA kit in Behring
Nephelometer BN-100. It was computed by using the
following formula: CDT% = 7.8 x (CDT/Total
Transferrin) - 0.2. For serum GGT level measurement,
blood samples of all patients were obtained from their
antecubital veins into anticoagulant-free test tubes at
admission. After serum samples were centrifuged at 4000
rpm for 10 min, GGT levels were measured by Szasz-
Persijn color test method in Roche Cobas Integra 400 plus
(Roche Diagnostic GmbH, Deutschland) using L-gamma-
glutamyl-3-carboxy-4-nitroanilide as substrate. For blood
MCV level measurement, blood samples were obtained
from antecubital veins to EDTA tubes. The MCV
measurements were performed by using Sysmex KX-21N
haemogram device.
Since subjects with alcohol withdrawal syndrome
demonstrating evident symptoms were included in the
study, a standard dose of 30 mg/day diazepam was
initiated in all patients and fluid-electrolyte balance was
maintained. Diazepam dose was given as mentioned in the
literature for patients with severe alcohol withdrawal
syndrome (20). Diazepam dose was reduced daily by 5
mg and discontinued at the end of the sixth day.
Memantine 10 mg/day was started in patients who were
previously randomized to the active drug group. The dose
was increased to 20 mg/day at the eight day and stopped
at the fifteenth day. Dose of memantine was given as its
dose in Alzheimer Disease. Currently the recommended
daily dose of memantine in Alzheimer Disease is 20mg
(10mg twice daily) (21). Corresponding amounts of
placebo were administered to patients in the control
group. Oral solution form of memantine was given to
study group and a colorless, clear, alcohol and sugar free
liquid was used as placebo. All medicines and placebo
were provided by researchers. Randomization procedures
and dose setting, administration of treatment and
questionnaires were performed by different investigators.
CIWA-AR was administered to all patients at the same
time of the day for each patient.
Statistics. SPSS 13.0 software was used for statistical
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C. Sengul, C. B. Sengul, T. Okay, N. Dilbaz
Table 1: Demographic characteristics of the participants
Memantine Group Placebo Group Mann Whitney-U test
(16 patients) (n) (%) (16 patients) (n) (%) P value
Age 45.8±8.7 43.6±7.3 0.76
Education (years) 8.5±3.5 9.1±3.4 0.51
Employment (fulltime) 12 (%75) 14 (%87,5) 0.65
Age of first alcohol use 18.2±4.8 19.7±5.4 0.82
Age of regular alcohol use 15.9±9.0 11.5±5.7 0.99
Drinks per day 22.2±7.8 19.6±6.1 0.347
History of epileptic seizures 5 (%31,3) 3 (%18,8) 0.41
History of delirium tremens 2 (%12,5) 2 (%12,5) 1
Alcohol Using Disorders Identity Test 37±3.4 35.1±4.6 0.17
Carbohydrate Deficient Transferrine 5.82 4.81 0.64
Mean Corpuscular Volume 96.7 98.4 0.36
Gama Glutamyl Transferase 138.8 193.2 0.69

analysis. Descriptive analysis was performed for
sociodemographic data. CIWA-AR scores comparisons of
groups were made by the Mann Whitney-U test.
Bonferroni correction was made for multiple testing.
(Bonferroni-adjusted p<0.01)
RESULTS
There were no significant differences between the
study and control groups in terms of age, educational
status, occupation, age at starting alcohol, mean duration
of alcohol use, and daily amount of alcohol consumption
(p>0.05). The mean baseline AUDIT score reflecting
drinking habits, alcohol consumption, and alcohol-related
problems was 37.0±3.4 for the study group and 35.1±4.6
for the control group. No statistically significant difference
was found between the groups for baseline AUDIT score
(p>0.05). The baseline mean CDT, MCV and GGT values,
that are objective biological markers used in the
assessment of alcohol dependency, were not statistically
different between the two groups (p>0.05). Baseline
characteristics of the study groups are presented in Table 1.
In order to assess the severity of withdrawal symptoms,
the CIWA-AR scale was administered to all patients by the
same, blinded investigator on the 1st, 4th 7th, 10th and
15th days at the same time of the day. CIWA-AR scores of
the first six days were not significantly different between
the groups when compared using the Mann-Whitney U test
(p>0.05). At the seventh day, CIWA-AR scores of the
memantine group were significantly different than the
control group. But when we made corrections for multiple
comparisons this significance disappeared. CIWA-AR
scores are presented in Table 2.
In this study we also compared the two groups
according to CIWA-AR item subscores on the 1st, 4th 7th,
10th and 15th days. Difference between the groups in
tremor (memantine 1,51±0,82, control 2,12±0,71) and
paroxysmal sweating (memantine 0,81±0,75, control
1,43±0,72) subscale scores on the fourth day were
significant. But this significance did not exist after
corrections for multiple comparisons (p>0.01). The
decrease in other subscale scores in the memantine group
were also higher but the differences were not statistically
significant (p>0.01).
DISCUSSION
In general, substances having cross-tolerance with
alcohol are used in the treatment of alcohol-related
withdrawal symptoms, and benzodiazepines are
frequently the first drug of choice all around the world
(22). Apart from benzodiazepines, many pharmacological
agents have been used in the management of alcohol
withdrawal syndrome. Although they are not used alone in
the treatment of alcohol withdrawal syndrome, these
agents may increase efficacy and decrease treatment
duration when used as supplementary drugs (23).
We used a NMDA receptor antagonist, memantine, as
an adjunctive drug in the treatment of alcohol withdrawal
syndrome in this study. We found that memantine group
had lower CIWA-AR scores during study periods. We also
found that CIWA-AR subscale scores such as tremor and
paroxysmal sweating were lower in memantine group on
measurement days. But when we compared groups
statistically, we found that addition of memantine to
standard alcohol withdrawal treatment did not cause any
statistically significant difference between these two
groups. There were a few studies in literature mentioning
the efficacy of memantine in alcohol withdrawal
syndrome and these studies differentiated from our study
with the study design and memantine doses. In one of
these studies Bisaga and Evans used memantine as a
pharmacological probe to look at the processes involved
in the effects of alcohol in moderate drinkers and reported
that memantine reduced the daily amount of alcohol
intake (14). In another study Evans et al. used memantine
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Memantine as an add-on therapy in alcohol withdrawal syndrome
Table 2: Average of CIWA-AR scores in measurement days
Day Memantine Group Placebo Group P value Z
1 23.63±7.24 22.94±7.47 .696 -0.32
4 7.88±4,37 8.63±4.79 .423 -1.08
7 2.44±2.03 4.19±2.10 .017 -2,27
10 0.94±0.99 2.50±1.82 .019 -2.69
15 0.25±0.44 1.13±0.96 .023 -0.11

in treatment seeking alcohol dependent individuals (15).
They looked whether it would reduce craving in a
dependent population in a 16 week treatment trial and did
not find a statistically significant difference between
memantine and placebo groups (15). In a study similar to
our study design, Krupitsky et al. found that memantine
30mg/day was effective in alcohol detoxification (16). In
the same study, they also found that lamotrigine and
topiramate were effective in alcohol detoxification and
suggested that antiglutamatergic approaches might be
useful in alcohol withdrawal syndrome (16). In this study,
different from ours, researchers used higher doses of
memantine without an additional medication. We might
speculate that if the study was designed in a way that
memantine would be used as a single therapeutic agent; it
might be possible to find statistically significant
differences between the memantine and placebo groups
starting from the first day. The combined use of
memantine and diazepam has probably concealed
observation of this finding.
Despite the advantages of this current study such as
the study population being chosen from hospitalized
patients and frequently performed assessments, our study
has some potential limitations. The main limitation is the
small sample size, 16 patients in study and control groups,
which precluded the use of parametric tests that would
provide more reliable statistical results. Secondly, since
memantine has not been approved to be used in the
management of alcohol withdrawal, doses that have been
approved for the treatment of dementia were used in our
study. Krupitsky et al. who used higher doses of
memantine, (30mg/day) found that it was effective in
alcohol withdrawal symptoms (15). This finding suggests
us that the required dose in alcohol withdrawal might be
higher. Controlled studies with flexible-dosing are needed
to address this issue.
In conclusion, preclinical and clinical studies mention
that anti glutamatergic medications are effective in
alcohol withdrawal syndrome. Despite the previous
reports that were mentioning that memantine was
effective in alcohol withdrawal syndrome; we did not find
statistically significant difference between these two
groups. Although memantine was not superior to placebo
in our study setting, randomized placebo controlled
studies with larger sample size and no additional
medication might be helpful for providing insights on the
efficacy of memantine and other antiglutamatergic agents
in alcohol withdrawal syndrome.
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C. Sengul, C. B. Sengul, T. Okay, N. Dilbaz
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Memantine as an add-on therapy in alcohol withdrawal syndrome