EtOH>> ↑ß-endorphin

↑ sensitifitas
↑ pelepasan ß-
EtOH>> sistem opioid
endorphin
endogen thd EtOH

mrgs pelepasan
CRH
• naltrexone, a nonspecific opioid antagonist, decreased
the craving for alcohol and relapse to heavy drinking.
• opioid deficiency hypothesis, opioid antagonists, by
binding to the opioid receptors and blocking the effects
of the endogenous opioid peptides, are creating an
opioid deficiency and should increase the craving for
alcohol instead of decreasing it.
• This apparent paradox may be explained by the high
doses of opioid antagonists used, which were sufficient
to occupy all opioid binding sites. Thus, even though
drinking would increase the release of opioid peptides,
they could not interact with their specific opioid
receptors to mediate the reward mechanisms that
eventually lead to a decreased craving for alcohol and
decreased relapse to heavy drinking.
 Stimulasi HT7 menurunkan asupan
alkohol
• modulation of the corticotropin releasing factor
and neuropeptide Y in the amygdala and the
GABA neuron in the ventral tegmental area (VTA).
• Menghambat p↓ neuropeptide Y (NPY) in the
central nucleus of amygdala (CeA) pada tikus EW
• attenuated ethanol withdrawal syndrome by
normalizing the dopamine release in nucleus
accumbens shell
• Inhibition of CORT Secretion during Ethanol
Withdrawal by Acupuncture
• increases in the concentrations of NE in the CEA
72 h after the last injection of ethanol in ethanol-
treated control rats when compared with saline
treated control rats (P < .01), whereas the
concentrations of DA and DOPAC in the CEA were
markedly decreased during ethanol withdrawal (P
< .01).
• Treatment with acupuncture at HT7 (P < .05 or
.01) but not PC6 (P > .05) significantly inhibited
the alterations of monoamines levels in the CEA
during ethanol withdrawal.
 central mechanism underlying
acupuncture’s role in drugs abused
• Modulation of GABAergic neurons in the ventral
tegmental area (VTA) through opioid receptors
and suppression of dopamine (DA) release in the
nucleus accumbens (NAc).
• acupuncture stimulates opioidergic neurons in
the arcuate nucleus of hypothalamus  opioids
released from the arcuate nucleus can activate
opioid receptors on accumbal GABA terminals
leading to a net decrease of DA transmission and
the reinforcing effects of abused drugs
 Beta-endorphin play a key role in a
mesolimbic reward system.
• mechanical acupuncture has a modulating effect on the
endogenous opioid system in alcohol addiction
• Endogenous opioid systems contribute to ethanol reward in
alcohol addicted rats
• blocking of endogenous opioid system is very effective for
treating alcoholism [24].
• Acupuncture related to the release of endogenous opioid
peptides (enkephalin, beta-endorphin and dynorphin) from
the central nervous system, and opioids are known to
increase dopaminergic neuron activity in the mesolimbic
brain region [7, 8].
• Acute withdrawal from chronic ethanol intake may
contribute to the reduced release of endogenous opioid
peptides and the excitability of dopaminergic neurons in
the VTA
 MA dan EA
• in functional brain mapping study, EA
produces more widespread signal increase
than MA.
• EA releases both β-endorphin and
adrenocorticotropic hormone in the blood,
whereas MA releases β-endorphin only
• Duration of stimulation EA>MA
Peripheral Afferent Mechanisms
Underlying Acupuncture
Inhibition of Cocaine Behavioral
Effects in Rats
Kim dkk. 2013

REFERENSI 16
• Administration of cocaine increases locomotor
activity by enhancing dopamine transmission.
• previous studies have shown that manual
acupuncture at acupoint Shenmen (HT7),
suppresses drug self-administration behavior
or relapse to abused drugs such as cocaine,
morphine and ethanol
 central mechanism underlying
acupuncture’s role in drugs abused
• Modulation of GABAergic neurons in the ventral
tegmental area (VTA) through opioid receptors
and suppression of dopamine (DA) release in the
nucleus accumbens (NAc).
• acupuncture stimulates opioidergic neurons in
the arcuate nucleus of hypothalamus  opioids
released from the arcuate nucleus can activate
opioid receptors on accumbal GABA terminals
leading to a net decrease of DA transmission and
the reinforcing effects of abused drugs
• several studies have implicated that the
effectiveness or the underlying mechanisms
between MA and EA are different. For
example, in functional brain mapping study,
EA produces more widespread signal increase
than MA.
• EA and MA differentially affect salivary flow
through releases of different types of
neuropeptides in healthy subj
• EA releases both β-endorphin and
adrenocorticotropic hormone in the blood,
whereas MA releases β-endorphin only
 SUPERFISIAL ATAU DALAM?
2. HT7 Acupuncture Involves Both Superficial and
Deep Nerve Activation
• EA analgesia in a rat anklesprain model is
produced by deep needling (3 mm) at SI5, but not
shallow (0.5 mm), indicating the generation of
acupuncture afferent signals from deep tissues
• inhibition of micturition contractions of the
urinary bladder: either superficial or deep tissues.
• Acupuncture inhibition of cocaine locomotion
was elicited by either superficial (1 mm) or deep
(3 mm) acupuncture at HT7
• 3. HT7 Inhibition of Cocaine-induced locomotion
Requires Activation of A-fibers in the ulnar
nerve
• afferent signals from acupuncture at ST36 for
producing analgesia are conveyed through A-
fibers of the perineal nerve
• Aδ fibers mediate analgesic effects of EA at SI5 in
ankle sprain model.
• MA and EA applied to PC5-6 acupoints activate
Aδ and C fibers to evoke cardiovascular effects
and blockade of C-fiber afferents using neonatal
capsaicin completely eliminates the
cardiovascular effects of EA
• 4. HT7 Inhibition of Cocaine-induced
locomotion Involves Activation of Pacinian
and Meissner Corpuscles
• Vibration stimuli are transmitted by
mechanoreceptors, Pacinian (200 Hz) and
Meissner corpuscles. 10~50 Hz
 Central Opioid Receptors
Differentially Regulate the
Nalmefene-Induced Suppression of
Ethanol- and Saccharin-
Reinforced Behaviors in Alcohol-
Preferring (P) Rats
June et al 2004
Referensi 23
• Higher densities of m-opioid receptor binding in
the nucleus accumbens (NACC) of P relative to NP
rats
• lower levels of m-receptor binding have been
observed in the ventral tegmental area (VTA) of
both P and NP rats
• The greater sensitivity of nalmefene (antag res
opioid) to suppress EtOH responding in the NACC
is likely due to the greater number of opioid
receptors in the NACC relative to the VTA
• nonselective opioid antagonists naltrexone and
nalmefene attenuate alcohol drinking behavior, control
craving, and prevent relapse in alcohol-dependent
humans
• Naltrindole, methylnaloxonium were ineffective when
infused into the VTA.
• local injection of methylnaloxonium into the nucleus
accumbens (NACC) and amygdala blocked EtOH self-
administration in outbred Wistar rats.
• Hyytia¨ and Kiianmaa (1997) evaluated the capacity of
the m-selective antagonist, CTOP, and the d1-receptor
antagonist, naltrindole to reduce EtOH maintained
responding when infused into the NACC, basolateral
amygdaloid nucleus (BLA), and ventral tegmental area
(VTA) in Wistar rats
• CTOP suppressed EtOH responding only when
injected in the BLA, while naltrindole
suppressed EtOH responding following
infusion into both the NACC and BLA.
• Both agents were ineffective when infused
into the VTA.
• Both m- and d-opioid recptors may
differentially regulate EtOH-maintained
responding in the NACC and BLA, but that
opioid receptors within the VTA do not appear
salient in regulating responding maintained by
EtOH.
Glial Cell Line-Derived Neurotrophic
Factor Reverses
Alcohol-Induced Allostasis of the
Mesolimbic Dopaminergic
System: Implications for Alcohol
Reward and Seeking
Barak et al 2011
REFERENSI 25
• infusion of glial cell line-derived neurotrophic
factor (GDNF) into the ventral tegmental area
(VTA) rapidly reduces alcohol intake and
relapse and increases dopamine (DA) levels in
the nucleus accumbens (NAc) of alcohol-naive
rats
• Withdrawal from excessive alcohol intake is
associated with a reduction in NAc DA levels,
whereas drug-induced increases in NAc DA
levels are associated with reward
 Critical Appraisal of Studies Using
Laboratory Animal Models
Annette M. O’Connor and Jan M.
Sargeant
ILAR Journal, Volume 55, Number 3,
doi: 10.1093/ilar/ilu038
• Bias seleksi: tidak ada
– tikus Wistar jantan 250 - 280 g ditempatkan dalam
kondisi yang sama
• Performance Bias: tidak ada
– Hewan dirawat dengan cara yang sama
• Detection Bias: tidak jelas siapa yang melakukan
pengukuran luaran
• Attrition Bias: tidak jelas
– Jumlah hewan awal dan akhir tidak ada keterangan
• Reporting Bias: tidak ada

28
 EXTERNAL VALIDIY
• The concept of external validity is a difficult
one in laboratory animal studies, because the
target population is unclear and varies by end-
user.
• By the very nature of using animals as models
for basic biological functions, there is the
implication that the results are in some way
generalizable to other populations, such as
humans.
 EXTERNAL VALIDIY
• In this paper we assume that the critical
appraiser has already made the decision that
the study results, if internally valid, will apply
to a target population.
• external validity often relates to the
population studied.
 INTERNAL VALIDITY
• “Are the results of the study population
representative of the source population?”
• Threats to internal validity occur due to bias.
• “Did the observed ratio or difference arise
because of the treatments, systematic bias, or
imprecision?” OR “What is the potential for
factors other than the variable of interest to
have influenced the results of the study?”
 BIAS
• Bias is caused by systematic errors
• The rationale for using the risk-of-bias
domains recommended by the Cochrane
Collaboration is that the biases associated
with animal research are consistent with those
associated with human health and animal
experiments more closely represent controlled
trials that observational studies.
 Risk-of-Bias Domains
• Selection Bias
– Sample: “Mice in the study were allocated to
treatment group by sex; treatment A consisted of
female mice and treatment B consisted of male mice”
– Definition: Systematic differences in baseline
characteristics between the treatment groups being
compared
– selection bias occurs when nonrandom factors
influence the allocation of animals to treatment
groups
– the sex of the group may account for the observed
difference in the group outcomes, rather than the
treatment. This is an example of selection bias
 Risk-of-Bias Domains
• Selection Bias
– “Are the groups comparable such that an observed
difference is likely attributable to the treatment rather
than a confounder?” A confounder is a factor that is
related to the outcome in the source population
independent of the treatments and related to the
treatments in the study population. A common
potential confounder in animal studies is sex. If the
sex of animals is unevenly distributed across the
treatment groups and sex has an effect on the
outcome, then the observed difference in treatments
may be simply a sex effect
 Risk-of-Bias Domains
• Selection Bias
– Randomization is the best known of the design tools to
balance the distribution of confounders across the
intervention groups
– randomization serves as an indicatorof a reduced riskof
bias. However, randomization does not guarantee the
balancing of confounders and, therefore, does not
guarantee the absence of selection bias as a cause of
observed group differences
– The reporting of randomization should not be treated as
synonymous with the absence of selection bias.
– The ability of randomization to balance both known and
unknown confounders decreases as the study becomes
smaller.
 Risk-of-Bias Domains
• Selection Bias
– The most commonly used design tool in laboratory
animal studies is restriction of the study population to
exclude a factor that is known to or would likely affect
the outcome.
– The groups are comparable such that an observed
difference is likely attributable to the treatment
rather than a confounder
– distribute confounders across intervention groups
restriction of the study population to exclude a
factor that is known to or would likely affect the
outcome: only conducting the experiment in male
mice
 Risk-of-Bias Domains
• Selection Bias
– Laboratory animal studies routinely are restricted to a source
population of the same age and genetic lines, and by doing so,
important known (or suspected) confounders are removed. It is
also important to recognize that the use of restriction as a
design tool means that variation is often lower in laboratory
animal studies compared with human randomized controlled
trials that are often designed to include a diverse group of
people. Because of this lower variation, restriction may in part
explain why large sample sizes are often not needed in
laboratory animal studies to observe differences.
Unfortunately, restriction also has the impact of reducing
external validity. Of note, the National Institutes of Health
recently have been discouraging restriction of studies to one sex
of animal (Clayton and Collins 2014).
 Risk-of-Bias Domains
• Selection Bias
– Where Might We Expect Information About
Selection Bias to Be in the Report?
– eligibility criteria for the study subjects, the
approach to allocation of study subjects to
treatment groups, the sample size, and the
baseline information for studysubjects in each of
the treatment groups (study population, housing,
and demographics and the baseline data of
animals in each treatment group)
 Risk-of-Bias Domains
• Performance Bias
– Performance bias occurs when there are systematic
differences between groups in the care that is provided, or
in exposure tofactorsotherthanthetreatment (Higgins et al.
2011).
– “Was the approach to husbandry the same for all
treatment groups and was caregiving done without
knowledge of the treatment group?” If the answer is no,
then the potential for performance bias may be high.
– First, the animals may be managed differently by design:
Location in facilities, group sizes, and diet
– Secondly, the animals may be managed differently by
nonblinded caregivers
 Risk-of-Bias Domains
• Detection Bias
– Detection bias can occur when there are systematic
differences between treatment groups in the way in
which the outcome is assessed
– “Was the approach to assessing the outcomes the
same in both groups and done without knowledge of
the group?” If the answer is no, the potential for
detection bias may be high.
– First, the animals may be managed differently by
design: Location in facilities, group sizes, and diet
– Secondly, the animals may be managed differently by
nonblinded caregivers
• Detection Bias
– The cages of the mice in the group treated with the
new fantastic drug were labeled with the term
“fantastic drug” and the cages of the mice that did not
received the treatment were labeled “old drug” Each
day the staff feeding the mice were asked to described
how active the mice where on a scale of 1 to 5, with 1
being not active and 5 being very active
• caregivers may have the expectation that the mice receiving
the new treatment will perform better and inadvertently
over estimate th eactivity levels of these mice
• The observed differences in the outcomes between groups
could be due to differential measurement of the outcome
between the 2 groups rather than treatment. This approach
clearly has the potential to introduce detection bias.
– The most common tool used to prevent detection bias
is blinding of the individuals assessing the outcome as
to which animals (or cages) belong to which treatment
groups
• Attrition bias
– refers to systematic differences in withdrawals from
treatment groups
– “Was the loss of animals from the groups minimal and
unrelated to the treatment groups?”
– The impact of attrition is that the outcome is not
observed for all animals
– If the outcome of those missing animals was
systematically different across the groups, then bias
can occur
– because only the healthy animals are actually
observed to the end of the study, the average weight
gain observed in treatment A is higher than the true
unobserved average, and the observed difference in
group averages is due to attrition bias rather than a
true treatment effect
• Attrition Bias
– the potential for voluntary attrition bias in laboratory
animal studies is almost nonexistent; however,
nonvoluntary attrition can occur if animals die or are
withdrawn because they met a priori criteria for
removal prior to observing the outcome
– The ARRIVE Guidelines propose that authors report
the number of animals enrolled in each group, the
number of animals completing the study, and the
number included in the analysis.
• Reporting Bias
– “Were the results of all outcome variables
assessed reported completely?”
 Involvement of amygdaloid
neuropeptide Y in the anxiolytic effects
of acupuncture during ethanol
withdrawal in rats
Zhao dkk, 2014
Neuroscience Letters 567 (2014) 19–
23
REFERENSI 12
• Neuropeptide Y (NPY) is widely distributed in
many brain regions, functions including
increasing food intake and reducing stress.
• NPY in the central nucleus of amygdala (CeA)
plays an important role in the mediation of
EW (ethanol withdrawal)-induced anxiety.
There is a significant reduction in NPY in the
CeA in ethanol-withdrawn rats
• acupuncture at HT7 attenuated EW-induced
anxiety via a modulation of CRF mRNA level in
the CeA
 Conclusions
• significant decrease in NPY protein and mRNA levels in the
CeA 72 h after the final dose of ethanol in rats.
• However, acupuncture at the specific acupoint HT7, but not
PC6 or a non-acupoint, restored these changes.
• Acupuncture at HT7 reversed the EW-induced decrease in
p-CREB in the CeA.
• intra-CeA infusions of a selective Y1 receptor, but not a
selective Y2 receptor, antagonist abolished almost
completely the anxiolytic effects of acupuncture at HT7.
• These results suggest that acupuncture at HT7 improves
amygdaloid NPY function via a normalization of CREB
activity which, in turn, produces anxiolytic effects during
EW in rats.
 Combined Pharmacotherapies and
Behavioral Interventions for Alcohol
Dependence The COMBINE Study: A
Randomized Controlled Trial

Anton, RF dkk.
JAMA. 2006;295:2003-2017
REFERENSI 1
• Patients receiving medical management with
naltrexone, CBI, or both fared better on drinking
outcomes, whereas acamprosate showed no
evidence of efficacy, with or without CBI.
• No combination produced better efficacy than
naltrexone or CBI alone in the presence of
medical management.
• Placebo pills and meeting with a health care
professional had a positive effect above that of
CBI during treatment.
• Naltrexone with medical management could be
delivered in health care settings, thus serving
alcohol-dependent patients who might otherwise
not receive treatment.
Enhanced Sensitivity of Pituitary β-Endorphin to
Ethanol in Subjects at High Risk of Alcoholism
Gianoulakis dkk.
(Arch Gen Psychiatry. 1996;53:250-257
REFERENSI 2
• Konsumsi EtOH >>  m↑ sensitifitas sistem
opioid endogen thd EtOH (memperantarai
efek penguatan EtOH)
• Pemaparan EtOH pada kel hipofisis & hipot 
m↑ pelepasan ß-endorphin
• EtOH mrgs pelepasan CRH  m↑
pelepasan ß-endorphin dari hipofisis & hipot
 ↑ sensitifitas
↑ pelepasan ß-
EtOH>> sistem opioid
endorphin
endogen thd EtOH

mrgs pelepasan
CRH
• ingestion of moderate doses of ethanol
induces a dose dependent increase in the
plasma ß-endorphin level of HR but not LR
subjects, suggesting an increased sensitivity of
their pituitary ß-endorphin system to ethanol,
a factor that could be important in mediating
ethanol's reinforcing effects.
• the influence of genetic factors in excessive
alcohol consumption.
• Endogenous opioid peptides such as ß-
endorphin, have been implicated in the
processes of reward and reinforcement.
• The major sites of ß-endorphin biosynthesis
are the pituitary gland and the arcuate
nucleus of the hypothalamus; corticotropin-
releasing hormone (CRH) increases the release
of both hypothalamic and pituitary ß-
endorphin peptides.
• the endogenous opioid system may mediate
some of ethanol's reinforcing effects.
• In vivo and in vitro exposure of the pituitary gland
and hypothalamus to ethanol demonstrated a
fast, transient increase of ß-endorphin release,
followed by an insensitivity of the tissues to
subsequent ethanol exposure for a period of
about 60 minutes.
• suggest that individuals at high risk of alcoholism
and animals exhibiting high ethanol con¬
sumption may have inherited an increased
sensitivity of the endogenous opioid system to
ethanol, presenting a more pronounced release
of opioid peptides following ethanol
consumption.
• ethanol stimulates the release of CRH and
ACTH, which in turn stimulate the release of
cortisol, increased release of cortisol is often
considered an indication of increased release
of CRH and ACTH. Since ACTH and ß-
endorphin share the same precursor and are
co-released from the pituitary gland under
various conditions," it may be expected that
an increase in plasma ß-endorphin level would
be associated with an increase in plasma
ACTH and cortisol levels
• the pituitary ß-endorphin system of the HR
subjects is more sensitive to ethanol than that of
the LR subjects
• "opioid deficiency hypothesis,"
– implication of the endogenous opioid system in
alcoholism is the HR subjects have inherited a
deficiency in the basal activity of the endogenous
opioid system.
– Since ethanol enhances the activity of the opioid
system, HR subjects consume high quantities of
alcohol to compensate for this deficiency.
– The lower basal levels of plasma ß-endorphin (shown
in this study), ACTH, and cortisol associated with
higher ß-endorphin response following ethanol
ingestion support this hypothesis.
• naltrexone, a nonspecific opioid antagonist, decreased
the craving for alcohol and relapse to heavy drinking.
• opioid deficiency hypothesis, opioid antagonists, by
binding to the opioid receptors and blocking the effects
of the endogenous opioid peptides, are creating an
opioid deficiency and should increase the craving for
alcohol instead of decreasing it.
• This apparent paradox may be explained by the high
doses of opioid antagonists used, which were sufficient
to occupy all opioid binding sites. Thus, even though
drinking would increase the release of opioid peptides,
they could not interact with their specific opioid
receptors to mediate the reward mechanisms that
eventually lead to a decreased craving for alcohol and
decreased relapse to heavy drinking.
• the release of ß-endorphin peptides by both
the pituitary gland and hypothalamus,
following exposure to various concentrations
of ethanol, presents an inverse U-shaped
dose-response curve, with low concentrations
(10 to 25 mmol of ethanol per liter) inducing a
more pronounced increase in the release of ß-
endorphin than high concentrations (30 to
120 mmol of ethanol per liter).
• moderate doses ofethanol used did not
demonstrate a biphasic pattern of ß-
endorphin release.
• lack of concordance between the ß-endorphin
and cortisol responses to ethanol. Since the
time course of stimulated cortisol secretion is
different from that of ß-endorphin, an
increase in cortisol release may have occurred
at a later time and was missed owing to
infrequent blood sampling.
• Ethanol may have altered the responsiveness
of adrenal cortex to pituitary ACTH.
Efficacy and safety of naltrexone and
acamprosate in the treatment of
alcohol dependence: a systematic
review

Carmen B, dkk.
REFERENSI 3
• acamprosate and naltrexone are effective as
adjuvant therapies for alcohol dependence in
adults. Acamprosate appears to be especially
useful in a therapeutic approach targeted at
achieving abstinence, whereas naltrexone
seems more indicated in programmes geared
to controlled consumption. Both drugs are
safe and acceptably tolerated but issues of
compliance need to be addressed adequately
to assure their usefulness in clinical practice.
•
• naltrexone exerts a competitive antagonism with
respect to the opioid receptors: this, in turn,
blocks the release of alcohol-induced dopamine,
thereby reducing the stimulus and reinforcing
effects of ethanol, and with it the ensuing craving
to drink and loss of control
• Acamprosate enhances GABA reception and the
transmission of the GABAergic system, reduced
by chronic exposure to alcohol, and interferes
with glutamate action in different pathways, such
as the N-methyl-D-aspartate (NMDA) receptors
• Acamprosate also acts on the calcium channels
and reduces central nervous system
hyperexcitability induced by suppression of
alcohol
• Naltrexone Standard dosage was usually 50
mg/day.
• Short-term therapy (12 weeks).
• administration of naltrexone was associated with
a significant improvement in the relapse rate
during the active treatment phase (Fig. 4) with an
NNT of 9 (95% CI: 6–14) as well as the follow-up
period (Table 4).
• although there was a trend to show favourable
effects on the abstinence rate during the active
treatment phase with naltrexone, the effect
estimation did not reach statistical significance
(Fig. 5). although this outcome was measured in
only two studies
• Naltrexone was associated with a statistically
favourable effect regarding the following
secondary outcomes: time to relapse;
percentage of drinking days; number of drinks
per drinking day; days of abstinence; total
consumption during treatment; and GGT and
AST levels (Table 5).
• In contrast, there were no differences vis-à-vis
the reference group in time to first intake or
percentage of carbohydrate-deficient
transferrin
• Medium-term treatment (6 months).
Landabaso et al.’s [43] results show naltrexone
as having a favourable effect on both
abstinence [OR (95% CI): 7, 49 (1.94, 32.52), P
= 0.004] and relapse rates [OR (95% CI): 0.18
(0.04, 0.78), P = 0.02]. No significant
differences were found between the
naltrexone and control groups in terms of
amount consumed [OR (95% CI): 1.1 (- 2.53,
0.33), P = 0.13] or degree of compliance [OR
(95% CI): 0.52 (0.11, 2.54), P = 0.4].
• naltrexone appears to reduce craving during the
treatment phase but that its possible beneficial
effect is lost during follow-up
• Medium-term treatment (6 months). Landabaso
et al.’s results show naltrexone as having a
favourable effect on both abstinence [OR (95%
CI): 7, 49 (1.94, 32.52), P = 0.004] and relapse
rates [OR (95% CI): 0.18 (0.04, 0.78), P = 0.02]. No
significant differences were found between the
naltrexone and control groups in terms of
amount consumed [OR (95% CI): 1.1 (- 2.53,
0.33), P = 0.13] or degree of compliance [OR (95%
CI): 0.52 (0.11, 2.54), P = 0.4].
• Long-term treatment (≥12 months). The
results reported by Krystal et al. [42] show no
differences between naltrexone and placebo
in terms of percentage of drinking days [WMD
(95% CI): 3.00 (- 7.80, 1.80), P = 0.2] or
number of drinks per drinking day [WMD (95%
CI): 0.30 (- 1.35, 1.95), P = 0.7] at 12 months of
treatment. In this study, no differences were
observed similarly at 12 months, as between
long- and short-term treatment with
naltrexone (drinking days 15.1 ± 23 versus
19.4 ± 26; drinks per drinking day: 9.6 ± 10
versus 10.5 ± 8).
• The most frequent side effects of naltrexone
were basically nausea (14% of patients),
sensation of dizziness (12% of patients) and
asthenia (10% of patients). Headaches were
common in both naltrexone and the
comparison group (15% and 16% of patients,
respectively).
• a significantly higher number of naltrexone-
treated patients withdrew from the studies
prematurely because of intolerance,
attributable in most instances to the
development of nausea
• Acamprosate versus naltrexone
– Adverse side effects, both gastrointestinal (41
versus 12 cases) and neuropsychiatric (25 versus
two cases), were higher in the group that received
naltrexone, and two patients withdrew from
treatment due to intolerance
– Acamprosate seems especially useful in a
therapeutic approach targeted at achieving
abstinence, whereas naltrexone seems more
indicated in programmes geared to controlled
consumption.
• short-term administration of naltrexone
significantly reduces the relapse rate to
excessive and destructive drinking as well as
outcomes linked to frequency of drinking and
amount consumed, but does not substantially
enhance abstinence
• during the active treatment phase with
naltrexone the number needed to treat was
nine, with 95% CI 6–14, for relapse avoidance
 The status of naltrexone in the
treatment of alcohol dependence:
Specific Effects on Heavy Drinking
Pettinati HM, dkk 2006
J Clin Psychopharmacol 2006;26:610–
625
REFERENSI 4
• naltrexone’s mechanism of action of
decreasing excessive drinking by reducing the
reward associated with drinking alcohol.
• Food and Drug Administration (FDA) in 1994
approving naltrexone for the treatment of
alcoholism in the United States.