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Drugs of Today 2011, 47(8): 575-581
Copyright © 2011 Prous Science, S.A.U. or its licensors. All rights reserved.
CCC: 1699-3993/2011
DOI: 10.1358/dot.2011.47.8.1617339
MONOGRAPH
BUPROPION/NALTREXONE FIXED-DOSE
COMBINATION FOR THE TREATMENT
OF OBESITY
B. Halpern, A.M. Faria and A. Halpern
Obesity & Metabolic Syndrome Unit, Division of Endocrinology & Metabolism, Hospital das Clínicas, University of
São Paulo Medical School, São Paulo, Brazil
CONTENTS
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .575
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .575
History of combination drugs and the rationale for their use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .576
Central control of appetite and the pro-opiomelanocortin pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .577
Bupropion and naltrexone: presentation and mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .577
Preclinical pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .578
Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .578
Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .578
Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .578
Drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .579
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .579
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .580
SUMMARY
The combination of bupropion and naltrexone is one of the
most promising new possibilities for the treatment of obesity in an era of increasing prevalence of this disease and
decreasing options for its pharmacological management.
Correspondence: Alfredo Halpern, Obesity & Metabolic Syndrome Unit,
Division of Endocrinology & Metabolism, Hospital das Clínicas, University
of São Paulo Medical School, Av. Dr. Enéas de Carvalho Aguiar, 255, 7º
andar, sala 7037, 05403-000 - São Paulo, SP, Brazil. E-mail:
[email protected].
Although approved by FDA panel members, it was temporally rejected by the FDA afterwards, who demanded more
cardiovascular safety data for its commercialization. This
monograph will focus on the physiology involved in its
mechanisms of action and results of clinical trials.
BACKGROUND
Although the prevalence of obesity has been dramatically increasing mainly in the western world during the last
four decades (1), the development and marketing of
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B. Halpern et al.
drugs for its treatment are still very unsatisfactory. In
Western Europe and the U.S., where more than one-third
of the population is obese, after the withdrawal of sibutramine due to the adverse events observed in SCOUT
(Sibutramine Cardiovascular Outcome Trial) (2, 3), only
orlistat is currently approved for long-term use, a drug
with only discrete efficacy in achieving weight loss (4).
Therefore, the nonsurgical treatment of obesity, in contrast with that for other chronic diseases like hypertension and diabetes, still relies on lifestyle modification,
which often fails and is difficult to maintain on a longterm basis (5).
It should be emphasized that obesity is much more than
an esthetic problem. The obesity epidemic is accompanied
by a significant increase in its related morbidities, such as
type 2 diabetes, hypertension and obstructive sleep
apnea, conditions that are well-known to be associated
with the development of cardiovascular disease, the leading cause of death in many developed and developing
countries (6), as in Brazil (7). Obesity is also associated
with an increased risk of some of the most common types
of cancers, such as colon, breast, gastric and endometrial,
among others (8). A recent study has shown a direct association between obesity and all cause mortality (9).
Accordingly, it is imperative to search for drugs that target
the causal factor and not only its consequences.
few years and apparently represents an effective and
safe treatment for obesity, with a physiologic rationale
for its use (11), although long-term data are still missing.
Despite being rejected by the FDA in February 2011 (12),
which demanded more studies to ensure its safety, this
combination will be extensively reviewed below, since we
believe it is important for public health to have new possibilities in the treatment of obesity.
HISTORY OF COMBINATION DRUGS AND THE
RATIONALE FOR THEIR USE
In a recent review, our group pointed out advantages and
disadvantages of combination therapy for the treatment
of obesity (10). Among the advantages of this approach
are an increased therapeutic efficacy due to synergic, additive action of both drugs; blockade of compensatory
mechanisms that leads to a weight loss plateau; and possibility of using lower doses that minimizes the chance of
adverse effects. On the other hand, potential disadvantages include undesirable drug interactions, higher costs
and dosage inflexibility in combination treatments.
The combination of drugs appears to be an interesting
option for the treatment of obesity, as it is a multifactorial disease, with environmental and genetic factors
linked and multiple pathways involved. Since some
pathways may be redundant and with different regulatory mechanisms, targeting only one, as in the case of
monotherapy, will probably not be enough to achieve
sustained weight loss (10).
The first combination widely used off-label in the U.S. in
the early 1990s was phentermine and fenfluramine (13).
Phentermine is a catecholaminergic drug that increases
the release of noradrenaline in the central nervous system (CNS) (14) and fenfluramine stimulates serotonin
release and inhibits its presynaptic reuptake (15), two
mechanisms involved in hunger and satiety control.
When they were used together, weight loss efficacy was
largely increased, apparently with fewer side effects.
Unfortunately, it was shown that this combination leads
to an increased risk of valvulopathy and pulmonary
hypertension, specifically due to fenfluramine, which was
withdrawn from the market in 1997 (16).
In this context, the combination of bupropion and naltrexone (Fig. 1) has emerged as a new option in the last
Although very few combinations have been studied in
randomized, placebo-controlled trials, such as sibu-
N
O
Cl
H
N
CH3
OH
CH3
CH3 .HCl
CH3
.HCl
HO
Bupropion hydrochloride
O
O
Naltrexone hydrochloride
Figure 1. Chemical structures of bupropion hydrochloride and naltrexone hydrochloride.
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B. Halpern et al.
tramine plus orlistat (17, 18), in a recent questionnaire,
85% of obesity specialists in the U.S. reported prescribing combinations of drugs and 65% prescribed drugs
not approved for obesity treatment (19). Considering the
lack of medications available for such a common disease, this report is definitely not surprising. This situation
illustrates the importance of developing new drugs and
combinations, bringing literature and clinical practice
closer, which ultimately will benefit patients.
Currently, a variety of combinations for obesity treatment
are in different stages of development and include the following: bupropion/naltrexone, phentermine/topiramate,
bupropion/zonisamide and pramlintide/metreleptin (10).
The FDA declined approval for phentermine/topiramate
due to safety concerns regarding birth defects and cardiovascular events (20). The bupropion/zonisamide combination has completed phase II development, while a
phase II trial of the pramlintide/metreleptin combination
was recently suspended to investigate a new antibodyrelated laboratory finding with metreleptin treatment
(21).
Bupropion/naltrexone received a positive review by FDA
panel members in December 2010 (22), but was rejected by the FDA (which normally ratifies the panel members’ decisions) in February 2011 (12), which decided that
the drug still needs more studies to ensure it does not
increase cardiovascular risk, a major concern after
SCOUT. It is surprising, if not worrisome, that despite the
increase in the prevalence of obesity and its related diseases, the FDA is continuously rejecting new antiobesity
drugs, as recently occurred with the combination of
phentermine/topiramate and with lorcaserin (20, 22,
23). Rimonabant, a cannabinoid CB1 receptor antagonist, is another weight loss agent not approved by the
FDA, but it was approved in Europe in 2006 and later
withdrawn from the market due to potential severe psychiatric side effects (24). In a recent editorial published
before the FDA’s rejection of bupropion/naltrexone,
eventual problems and incongruences were outlined in
the process of antiobesity drug approvals by FDA members that deserve consideration (25).
CENTRAL CONTROL OF APPETITE AND THE PROOPIOMELANOCORTIN PATHWAY
Central mechanisms of hunger and satiety are regulated
by the arcuate nucleus of the hypothalamus, which
receives signals by dozens of hormones and peptides,
synthesized mainly by the gut and adipose tissue, like
insulin, leptin and ghrelin (26).
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BUPROPION/NALTREXONE
The arcuate nucleus is divided into a lateral and a medial portion which work in opposite pathways, but transmit
signals to the same areas of the brain (11). The lateral
neurons synthesize and secrete neuropeptide Y and
Agouti-related protein, with orexigenic actions, while
medial neurons produce pro-opiomelanocortin (POMC),
which is rapidly cleaved into melanotrophin alpha (αMSH) and β-endorphin. α-MSH acts at melanocortin
MC3 and MC4 receptors in the hypothalamus and the
rest of the brain, inducing satiety and inhibiting food
intake, as well as increasing rest expenditure. On the
other hand, β-endorphin, an endogenous opioid, autoinhibits the POMC pathway and its excess in rodents leads
to increased food intake (11).
BUPROPION AND NALTREXONE: PRESENTATION
AND MECHANISMS OF ACTION
Since 1979, when naloxone, a classical opioid receptor
antagonist, was found to induce a significant reduction
in food intake in mice (27), it has been believed that
opioids have a role in appetite regulation. In addition,
opioid receptor agonists induce food intake in rodents
and the ingestion of palatable foods activates β-endorphin release in these animals (28). These findings led
to the opioid-palatability hypothesis, in which the opioid release makes the food more palatable and the
ingestion of palatable foods facilitates this release,
although few data in humans support this hypothesis
(28).
Naltrexone is a drug approved for the treatment of opioid and alcohol dependence. The drug and its active
metabolite, 6-β-naltrexol (metabolized in the liver by
dihydrodiol dehydrogenase and eliminated by the kidneys), are competitive antagonists of μ- and κ-opioid
receptors. Its major side effects are nausea, headache,
dizziness, anxiety and fatigue (28).
Although some reports commented a possible decrease
in food intake and weight loss with naltrexone, its use as
monotherapy in obesity is not associated with significant
weight loss (28).
Bupropion is a norepinephrine and dopamine reuptake
inhibitor used mainly for the treatment of depression
and smoking cessation (29). It is proposed that the higher levels of dopamine and norepinephrine in the arcuate
nucleus can fire POMC neuron signaling and lead to
appetite suppression (11). Bupropion alone was studied
for the treatment of obesity with a placebo-subtracted
weight loss of 3-5 kg with an early plateau. This plateau
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can be explained by a compensatory feedback, with an
increased production of β-endorphin (30).
Considering the mechanisms of action of both drugs, it
was proposed that inhibition, mediated by naltrexone, of
the autoinhibition of a bupropion-stimulated POMC
pathway could result in better and more sustained
weight loss than either drug alone (11).
PRECLINICAL PHARMACOLOGY
The formulated hypothesis above was first tested in electrophysiological studies (11). It was shown that, when used
together, bupropion and naltrexone increased the firing
frequency of POMC neurons to a greater extent than either
drug alone, suggesting a synergic mechanism.
The combination was also studied in animal models with
lean and obese mice. In obese mice, while bupropion
and naltrexone alone reduced food intake by 27 and
49%, respectively, the combination resulted in a 94%
reduction. In lean mice, similar results were noted, with
the combination reducing food intake by 77%, compared
with 34 and 67% with bupropion and naltrexone, respectively (11). Administration of the drugs into the ventral
tegmental area, alone and in combination, also led to a
synergistic reduction in food intake (31).
PHARMACOKINETICS
Bupropion undergoes hepatic metabolism via cytochrome P450 (CYP) 2B6, being converted mainly to
hydroxybupropion, which has a lower (20-50%) potency.
Bupropion sustained-release (SR) formulation has a
peak after 6 to 7 hours. Other metabolites formed by
non-CYP-mediated pathways, erythrohydrobupropion
and threohydrobupropion, remain in blood for around 35
hours, but can last for as long as 60 hours (32).
Naltrexone, as mentioned above, is metabolized to 6-βnaltrexol in liver, which has a renal excretion (28).
Bupropion SR/naltrexone SR 270/37.5 mg p.o. was
compared with bupropion SR/naltrexone immediate
release (IR) 270/36 mg p.o. in a phase I randomized
study in patients with uncomplicated obesity. There was
a reduction in the Cmax value with the combination containing naltrexone SR and comparable AUC values
between them (31).
SAFETY
The main adverse events of the combination are nausea,
constipation, headache, dizziness, fatigue, vomiting and
dry mouth (11, 31, 33, 34).
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In the Contrave Obesity Research-I (COR-I) and COR-II
studies together (described below), three serious events
were reported, possibly related to the use of one component of the combination: seizure (one), paresthesias
(one) and palpitations with dyspnea and anxiety (one)
(33). It should be overemphasized that bupropion is contraindicated in patients with a previous history of
seizures and this was in fact an exclusion criterion in
both studies.
CLINICAL STUDIES
A first phase II study was developed to validate these
results in humans. Bupropion SR 300 mg was combined
with naltrexone IR 50 mg and this combination was
compared with either drug alone or placebo with promising results (11). A larger phase II study was then conducted to test different dosages: 400 mg SR bupropion
combined with either 16, 32 or 48 mg IR naltrexone
(NB16, NB32 and NB48, respectively) (35). Similar control groups were used. In 24 weeks the weight loss by
intent-to-treat analysis was 5.4, 5.4 and 4.3% for the
combination of bupropion with NB16, NB32 and NB48,
respectively, against 2.7% for bupropion monotherapy,
1.2% for naltrexone monotherapy and 0.8% for placebo.
The lower weight loss seen in the patients receiving
NB48 was justified by the higher dropout rate (63%) due
to side effects in this group. After 24 weeks, there was no
sign of a plateau in any of the three combination groups.
Patients receiving bupropion alone or the three doses of
the combination were followed for an additional 24week extension, and in the final analysis at 48 weeks, the
NB32 combination reached a higher success rate with an
average weight loss of 6.6%. It was also found in other
phase II studies that naltrexone SR resulted in fewer side
effects compared with the IR formulation.
Based on these results, phase III studies were designed
accordingly, using a daily dose of 16 and 32 mg/day SR
naltrexone and 360 mg SR bupropion, divided on a
twice-daily basis.
The COR-I trial (NB-301) randomized 1,742 patients to
NB16, NB32 or placebo, with 4 weeks of titration of medication and a duration of 56 weeks (36). The placebosubtracted weight loss was 3.7 and 4.8% for NB16 and
NB32, respectively. In the NB32 group, 48, 25 and 12% of
the patients lost more than 5, 10 and 15%, respectively,
compared with 39, 20 and 9% with NB16 and 16, 7 and
2% in the control group.
The weight loss in the treatment groups began earlier, in
the fourth week, and was sustained during the 56 weeks,
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B. Halpern et al.
with a maximal weight loss achieved between weeks 28
and 36.
Improvements from baseline in waist circumference,
insulin resistance, HDL-cholesterol, triglycerides and
high-sensitivity C-reactive protein were also seen in the
treatment groups. NB32 was also associated with an
improvement in fasting glucose and insulin compared
with placebo.
Dropout rates due to adverse reactions were approximately 20% in the treatment group, compared with
9.5% in the placebo group. Dropout due to insignificant
weight loss was 2% in the treatment groups versus 7%
with placebo. The total dropout was similar in all groups,
and was around 50%.
The most commonly observed side effect was nausea,
around 30%, compared to 5 and 6% in the placebo
group. The incidence occurred mainly in the initial weeks
of treatment, still within the titration phase, with a tendency to fall after the fourth week. Other side effects significantly more common than placebo, in order of frequency, were constipation, headache, dizziness, vomiting
and dry mouth. There was no significantly higher incidence of adverse events on the cardiovascular system,
nor in relation to depressive disorders or suicidal ideation.
The blood pressure of patients using the combination
remained unchanged after 56 weeks, with a slight
decrease of 2 mmHg in the placebo group, and a negligible increase of one beat per minute in the heart rate of
the treated patients. On the other hand, greater weight
loss was associated with greater reduction in blood pressure in the treatment groups.
The COR-II trial (NB-303), yet to be published, compared
only NB32 with placebo (37). More patients were randomized to the treatment group (n = 1,001) and the
results reported by the pharmaceutical company developing the drug were similar to those seen in COR-I (38).
Another recent trial named COR-BMOD (Contrave
Obesity Research-Behavior Modification; NB-302) was
designed to assess the impact of NB32 when associated
with intensive lifestyle and behavior modifications
(BMOD), again during 56 weeks (39). All participants
received counseling from behavioral psychologists, dietitians and exercise specialists and were prescribed a lowcalorie diet and moderate physical activity, up to 360
min/week. They were also encouraged to keep a record
of their activity.
In total, 202 patients were randomized to placebo plus
BMOD and 591 to BMOD plus NB32. The total weight
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BUPROPION/NALTREXONE
loss seen in the treatment group in patients that finished
the 56 weeks was 11.5%, which accounts for a placebosubtracted weight loss of 4.2%. Discontinuation of treatment due to adverse events was 25.2% for NB32 and
12.4% for placebo.
Percentages of 5, 10 and 15% of weight loss in completers was 80.4, 55.2 and 39.5% in the NB32 group
compared with 60.4, 30.2 and 17.9% in the placebo
group. In all patients (including noncompleters), the
numbers were 66.4, 41.5 and 29.1% for NB32 and 42.5,
20.2 and 10.9% for placebo. As in COR-I, greater reductions were seen in markers of cardiovascular risk, such as
triglycerides, waist circumference and fasting insulin as
well as an increase in HDL-cholesterol levels. Blood
pressure lowered in both groups, but more with placebo.
The main adverse events were similar to those seen in
COR-I. In summary, NB32 proved to be an effective drug
to induce weight loss even in patients who dramatically
changed their lifestyles during a 56-week program.
Another trial, COR-Diabetes (NB-304), also not yet published, was conducted to verify changes in diabetic
patients’ profiles. A small, but significant, placebo-subtracted reduction of 0.5% in HbA1c was observed (40).
More clinical trials have been done with the combination, with results pending until now, including in patients
with major depression and nicotine dependence (41, 42).
Results from another study that used functional magnetic resonance imaging to assess possible effects on
brain function from the combination on food craving and
food intake are also to be published (43).
DRUG INTERACTIONS
Bupropion, due to its increased risk of seizures, should
be used with caution with other CNS-acting drugs, such
as selective serotonin reuptake inhibitors and catecholaminergic drugs, as well as with any particular drug
that can reduce seizure threshold (44). Its use should be
avoided in patients receiving monoamine oxidase
inhibitors.
Naltrexone has no known significant interactions. It
should not be used in patients who need opioid treatment.
CONCLUSIONS
Undoubtedly, obesity is a major health problem that in
many cases should be treated with drugs. As in other
chronic diseases, the combination of drugs for obesity
may be an important treatment strategy. The association
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BUPROPION/NALTREXONE
of bupropion and naltrexone has a scientifically rational
basis that was proved effective in large clinical trials and
may be useful for many obese patients.
Unfortunately, regulatory agencies’ opinions of antiobesity drugs seem to be more severe than those for treatments for other diseases, and this situation possibly justifies the attitude of the FDA, which is not approving the
drug for the moment despite a positive review by FDA
panel members.
DISCLOSURES
The authors state no conflicts of interest.
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