ICAN: Infant, Child, & Adolescent Nutrition

ICAN: Infant, Child,
& Adolescent Nutrition
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Drugs and Appetite : An Overview of Appetite Stimulants in the Pediatric Patient
Kathleen Gura and Roselle Ciccone
ICAN: Infant, Child, & Adolescent Nutrition 2010 2: 358
DOI: 10.1177/1941406410387925
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December 2010
ICAN: Infant, Child, & Adolescent Nutrition
Evidence-Based Practice Reports
Drugs and Appetite
An Overview of Appetite Stimulants
in the Pediatric Patient
Kathleen Gura, PharmD, and Roselle Ciccone, PharmD candidate
Abstract: A poor appetite can negatively impact growth and neurodevelopment. In some cases, it may be
necessary to use pharmacologic agents
to stimulate the child’s appetite.
Unfortunately, experience using these
drugs in the pediatric patient is limited
at best. Most agents have side effects
that limit their usefulness solely as an
appetite stimulant. The purpose of this
article is to review the current agents
used for this indication in adults and
consider the advantages and disadvantages of each when used in a pediatric
patient. Other factors such as taste
perversion secondary to medication use
will also be briefly discussed.
Keywords: anorexia; appetite stimulation;
cyproheptadine; dronabinol; megesterol
L
oss of appetite is described as a loss
of desire to eat. Significant weight
loss can occur and long-term nutrition may be affected, leading to weakness
and fatigue that can not only inhibit daily
activities but can also lead to malnutrition,
consequently increasing the risk of morbidity and mortality. Children with intestinal failure, those who have undergone a
transplant, and those who have cancer or
cystic fibrosis are often at risk.
Pharmacological treatments (Table 1)
have been studied extensively in adults
for their use as appetite stimulants; however, studies in the pediatric patient are
lacking. To date, the most commonly
studied syndrome focuses on anorexia/
cachexia in the oncology population.
Most of these results have been extrapolated to other groups; however, this disease state is directly associated with
several specific chronic physiological processes related to the cancer growth and
also sustain weight gain or prevent nausea and emesis, leading to a higher tolerability for food. The primary types of
treatment modalities that have been used
include agents with orexigenic (appetite
stimulating), anticatabolic (antimetabolic
and anticytokine), or anabolic (hormonal)
properties.1 Unfortunately, most of the
evidence to date is limited to adult
patients; so use of these agents in the
pediatric patient must be done with
extreme caution as many have significant
“Pharmacological treatments have been
studied extensively in adults for their use
as appetite stimulants; however, studies
in the pediatric patient are lacking.”
introduction of chemotherapeutic agents.
Thus, it is often difficult to ascertain
whether the same results would be seen
in other populations. What follows is a
review of the evidence surrounding appetite stimulation and the role pharmacological agents may have. It is important to
note that some of the agents discussed
may not only stimulate appetite but may
side effect profiles that can outweigh any
potential benefits.
Corticosteroids
For years, corticosteroids have
remained the mainstay of therapy for
appetite stimulation. It has been demonstrated that steroid use can cause
DOI: 10.1177/1941406410387925. From Children’s Hospital Boston (KG); Northeastern University (RC), Boston, Massachusetts. Address correspondence to Kathleen Gura,
Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115; e-mail: [email protected]
For reprints and permissions queries, please visit SAGE’s Web site at http://www.sagepub.com/journalsPermissions.nav.
Copyright © 2010 The Author(s)
358
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How Supplied
Tablets: 10, 25, 50,
75, 100, 150 mg
Tablets: 4 mg; syrup:
2 mg/5 mL
(5% alcohol)
Drug
(Trade Name)
Amitriptyline
(Elavil, others)
Cyproheptadine
(Periactin)
Give at bedtime to minimize sedation or drowsiness after dose
May give with food to decrease GI upset, may be better choice for those with difficulty
sleeping or diarrhea
Do not discontinue abruptly; may cause withdrawal symptoms (headache, nausea,
malaise)
Anticholinergic (urinary retention, worsening of
GE reflux, decreased lower esophageal sphincter
tone constipation, dry mouth, dizziness, blurred
vision)
Sedation
Arrhythmia, tachycardia, increased QT
interval, postural hypotension
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Administer with food
(continued)
Typical dosing: Children >13 years and adults: 2 mg 4 times/d; may be increased
gradually over a 3-week period to 8 mg 4 times/d
Others: dry mouth, urinary retention, blurred
vision
Contraindicated in children with asthma, GI/GU obstruction, glaucoma
Antihistamine, may be used to stimulate appetite in anorexia, may also be used for
migraine prophylaxis
Sedation, headache, seizures; photosensitivity;
tachycardia; appetite stimulation, nausea,
diarrhea
Do not use MAO inhibitors within 14 days of stopping amitryptyline
Do not combine with MAO inhibitors or St John’s Wort, additive effect with other
CNS depressants
CYP 450 substrate—involved in many drug interactions
Consider baseline ECG, may choose to follow BP, CBC, ECG with dose changes
Caution for use in children with cardiovascular disease, seizures, urinary retention,
anorexia, renal or hepatic dysfunction, hyperthyroidism
May discolor urine to blue/green
Clinical Implications
Worsening of depression or suicidal ideation
and behavior—should not be used for
children with underlying depression unless
under supervision of appropriate psychiatric
specialist
Adverse/Side Effects
Examples of Medications That Have Been Used as Appetite Stimulants
Table 1.
vol. 2 • no. 6
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360
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Tablet: 10 mg
Capsules (strength
varies)
Ginger powder
Soft gelatin capsule:
2.5, 5, 10 mg;
contains sesame oil
How Supplied
Fluoxymesterone
(Androxy)
Dronabinol
(Marinol)
Drug
(Trade Name)
Table 1. (continued)
Typical dose used for appetite stimulation in adult AIDS patients: 2.5 mg twice daily
(before lunch and dinner), with dosage adjustments based on efficacy or side
effects, up to 20 mg maximum daily
Central nervous system: drowsiness,
dizziness, vertigo, difficulty concentrating,
mood changes, euphoria, detachment,
depression, anxiety, paranoia, hallucinations,
nervousness, ataxia, headache, memory
lapse, seizures, fatigue, nightmares
(continued)
Use with caution in individuals with a history of bleeding or hemostatic disorders
In prepubertal children, perform radiographic examination of the hand and wrist every
6 months
May cause amenorrhea in females, hirsutism,
acne, testicular atrophy in males
Abdominal discomfort, “bad taste,” belching,
bloating, flatulence, heartburn, nausea,
“pepper-like” esophageal irritation,
and transient burning sensation of the
tongue have been reported (primarily with
powdered forms of ginger)
Pregnancy risk factor X: Determine that patient is not pregnant before beginning
treatment. Instruct patients of child-bearing age on appropriate contraceptive
measures during therapy and for 1 month following therapy. Breast-feeding is
contraindicated
May accelerate bone maturation without
producing compensatory gain in linear
growth in children
Use with caution in patients with mania or depression as dronabinol may exacerbate
these conditions
Tolerance to CNS side effects usually occurs in 1 to 3 days of continued use;
tachyphylaxis and tolerance does not appear to develop
Reduce dosage in patients with severe hepatic impairment
Use with caution in patients with seizure disorders (may lower seizure threshold)
Pediatric dosing not established for this indication but doses of 5 mg 3 or 4 times
daily has been used as an antiemetic
Take before meals to stimulate appetite
Reduce dosage in patients with significant hepatic dysfunction
Drug interaction/additive sedative effects with MAO inhibitors, other CNS depressants
and anticholinergics
Clinical Implications
Cardiovascular effects: orthostatic
hypotension, tachycardia, palpitations,
hypotension, flushing
Adverse/Side Effects
ICAN: Infant, Child, & Adolescent Nutrition
December 2010
Tablets: 20 mg,
40 mg; Suspension:
40 mg/mL; Megace
ES: suspension:
125 mg/mL
Tablets: available in
variety of strengths
Melatonin
How Supplied
Megesterol
(Megace)
Drug
(Trade Name)
Table 1. (continued)
A synthetic progestin: may be recommended for appetite stimulation in patients with
significant anorexia, failure to thrive, or cachexia
Typical dosing as an appetite stimulant in cachexia: titrate dosage to response;
decrease dose if weight gain is excessive
Flatulence, dyspepsia rash, fever,
hypertension, insomnia, hyperglycemia
Photosensitivity reaction possible
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Adults experience about a 37% decline in daily melatonin output between 20 and 70
years of age
Excessive dosages may cause morning
sedation or drowsiness
(continued)
Melatonin is the primary sleep-regulating hormone of the body; it is secreted in
concert with normal day/night cycles
No known toxicity or serious side effects
reported
Megace ES is not equivalent mg per mg with other megestrol formulations
(625 mg Megace ES is equivalent to 800 mg megestrol tablets or suspension);
suspensions contain alcohol
Clinical cases of new onset diabetes mellitus, exacerbation of preexisting diabetes
mellitus, and overt Cushing syndrome have been reported in association with the
chronic use of megestrol acetate
Evidence of adrenal suppression has been observed in patients receiving megestrol
acetate oral suspension
May lead to adrenocortical insufficiency if withdrawn abruptly
Contraindicated in pregnancy, may cause fetal harm
Caution in patients with diabetes or thromboembolic disease
Adolescents and adults: megestrol (tablets or 40 mg/mL suspension): 800 mg/d
in 1 to 4 divided doses; titrate dose to response; doses between 400 and 800 mg/d
have shown efficacy; Megace ES: 625 mg once daily
Children: limited data have been reported in cachectic children with cystic fibrosis,
HIV, and solid tumors: 7.5 to 10 mg/kg/d in 1 to 4 divided doses; not to exceed
800 mg/d or 15 mg/kg/d
Discontinue use prior to dental or surgical procedures (at least 14 days prior)
Clinical Implications
Very high doses may inhibit platelet
aggregation
Adverse/Side Effects
vol. 2 • no. 6
ICAN: Infant, Child, & Adolescent Nutrition
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Tablet: 4 mg, 8 mg,
24 mg; solution:
4 mg/5 mL;
injection:
2 mg/mL; infusion:
32 mg/50 mL
Ondansetron
(Zofran)
At least 14 days should elapse between discontinuation of an MAO inhibitor and
initiation of therapy with mirtazapine; at least 14 days should be allowed after
discontinuing mirtazapine before starting an MAO inhibitor
Hypertriglyceridemia
Dry mouth, bradycardia, abdominal pain,
lightheadedness
Some products may contain phenylalanine
Somnolence
Some products may contain phenylalanine
Take without regard to meals
May cause significant xerostomia (normal salivary flow resumes on
discontinuation)
In adults, the average dose ranged from 15 to 45 mg/d
Therapy durations >12 weeks should be avoided
May cause tardive dyskinesia, which is often irreversible; duration of treatment and
total cumulative dose are associated with an increased risk
Administer 30 minutes before meals and at bedtime
Doses of 1 to 3 mg/kg may be used to prevent nausea (significantly higher than
reflux dosing), but close monitoring necessary to avoid side effects
Should be taken at bedtime; in adults, doses of 20 mg/d have been used
Clinical Implications
Has potential for psychological or
physiological dependence, abuse, or
tolerance
Drowsiness, restlessness, anxiety, agitation,
tardive dyskinesia, dystonia, constipation,
diarrhea
Use with caution in individuals using CNS
depressants as concurrent use may cause
additive sedation
Adverse/Side Effects
Abbreviations: GE, gastroesophageal; GI, gastrointestinal; ECG, electrocardiogram; BP, blood pressure; CBC, complete blood count; MAO, monoamine oxidase; CNS, central nervous system.
Tablet, oral: 7.5 mg,
15 mg, 30 mg,
45 mg; Tablet, orally
disintegrating:
15 mg, 30 mg,
45 mg
Syrup: 1 mg/mL;
tablet: 5 mg,
10 mg; injection:
5 mg/mL
How Supplied
Mirtazapine
(Remeron)
Metoclopramide
(Reglan)
Drug
(Trade Name)
Table 1. (continued)
ICAN: Infant, Child, & Adolescent Nutrition
December 2010
vol. 2 • no. 6
significant weight gain; thus, these agents
have been studied extensively for this
purpose. The exact mechanism has not
been established but may be related to
the euphorgenic and anti-inflammatory
effects. It has been postulated that
stimulation of the orexigenic hormones
within the hypothalamus may also be
responsible for this increase in appetite.1
For example, several studies have been
done evaluating prednisolone as an
appetite stimulant in oncology patients
and its effects on energy metabolism.2,3
Overall, prednisolone seems to be an
effective agent in stimulating appetite on
a short-term basis; however, it was not
shown to be beneficial for long-term
weight gain. Because of the long-term side
effects associated with steroids, practitioners often struggle whether the benefits of
an improved nutritional state outweigh the
long-term risks seen with their use. In one
such study, Lai et al3 compared prednisolone to megestrol acetate (to be discussed
later). They showed that although both
agents seemed to stimulate appetite in
this small population, megestrol proved to
be statistically significant when compared
with placebo, whereas prednisolone was
not. Another study by Tataranni et al4
discussed the effects of glucocorticoids on
energy metabolism based on norepinephrine levels (to estimate sympathetic
nervous system activity) and indirect
calorimetry in healthy individuals. This
study showed an increase in energy
intake and suggested that this could be
the reason behind the weight gain that is
typically seen.
The first randomized controlled trial with
glucocorticoids was done by Ho et al5
using dexamethasone. Similar to the
aforementioned studies, it was conducted
in the oncology population and focused
mainly on its use to prevent chemotherapyinduced nausea and vomiting. The authors
suggest that the clinical improvements
seen with dexamethasone were a reflection of its antiemetic properties as well
as its tendency to promote weight gain.
In animal studies, it was shown that
dexamethasone’s antiemetic actions may
be partially due to its activity in the central
nervous system (CNS) and may be related
to its activation of glucocorticoid receptors
ICAN: Infant, Child, & Adolescent Nutrition
in the nucleus of the medulla.5 Two
studies suggest that although dexamethasone may stimulate appetite in the short
term and increase nonfluid weight
changes transiently, its use is associated
with steroid toxicity, which often results in
patients discontinuing therapy with no
apparent significant difference in
mortality.6,7 In a head-to-head trial with
megestrol, the results again favored the
latter.6 Although dexamethasone has not
been proven to enhance weight gain and
appetite in the long term, it is still an
effective antiemetic agent that can be
helpful for patients undergoing chemotherapy and ultimately enable them to
tolerate food better, thus indirectly leading
to appetite stimulation.
Some side effects associated with
corticosteroids include hyperglycemia,
hyperlipidemia, immunosuppression,
Cushingoid syndrome, hypothalamic–
pituitary–adrenal axis suppression, peptic
ulcers, and neurological effects. Longterm use of glucocorticoids can lead to
loss of bone and deterioration in
short-term growth.7-9 Glucocorticoids
have a suppressive effect on osteoblastogenesis in the bone marrow and
promote the apoptosis of osteoblasts and
osteocytes, thus leading to decreased
bone formation.10 Furthermore, highdose glucocorticoid therapy can
attenuate physiological growth hormone
secretion via an increase in somatostatin
tone.11,12 Glucocorticoid-induced growth
failure may also be due to direct effects
on the growth plate.13-16 Based on these
findings, it is suggested to limit steroid
use in children to as short a course as
possible to avoid these complications.
Central Nervous
System Drugs
Dronabinol (delta-9-tetrahydrocannabinol)
works by acting as an agonist for the
bodies’ endocannabinoid systems, on
receptors CB1 and CB2.17 The CB1
receptors are located in the feedingrelated hindbrain area, as well as
gastrointestinal, adipose, and hepatic
tissues, and may have an influence on
appetite. Dronabinol is currently approved
by the Food and Drug Administration
(FDA) for use as an appetite stimulate in
adult AIDS patients.18 Dronabinol is also
FDA approved for the prevention of
cancer-related nausea and vomiting in
both adults and children. Side effects
associated with dronabinol use include
short-term memory loss, dizziness,
euphoria, paranoid reaction, tachycardia,
and vasodilation.18 It should not be used
in patients allergic to sesame. There has
yet to be extensive studies of dronabinol
for appetite stimulation in the pediatric
population. Abrahamov et al19 used a
different cannabinoid (delta-8-THC instead
of delta-9-THC) with good results. Over a
2-year period, 8 children with various
types of leukemia were administered
delta-8-THC 18 mg/m2 by mouth 2 hours
before chemotherapy treatment and
continued every 6 hours for 24 hours,
and all vomiting was prevented.
Antidepressant agents may be considered in patients with an underlying
psychological issue present. Overall, these
drugs are not recommended for use as
appetite stimulants because of their broad
range of side effects and lack of efficacy
and safety data in the pediatric population. For example, tricyclic antidepressants (TCAs) are a class of CNS agents
known to cause weight gain in patients
receiving them chronically. They work by
increasing the synaptic concentration of
serotonin and/or norepinephrine in the
CNS by inhibiting their reuptake. One of
the major complications seen with this
class of drugs is their anticholinergic
effects, which have been implicated as a
mechanism for TCA-associated weight
gain. The theory is that because of
xerostomia associated with TCA use,
excessive intake of high-calorie beverages
occurs, along with an increased craving
for other carbohydrates.
The most widely studied TCA is
amitriptyline. It has been studied for its
effects on body mass and in patients with
anorexia nervosa. In one study by Paykel
et al,20 involving 51 females, the average
weight gain was 4 kg; other studies have
shown up to a 7 kg weight gain.21 In the
Paykel et al20 study, many subjects
reported cravings for carbohydrates at the
beginning of the second month of therapy.
In both studies, patients were on long-term
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December 2010
ICAN: Infant, Child, & Adolescent Nutrition
therapy; weight gain was not observed in
the initial phase of treatment. In another
double-blind, placebo-controlled study
using amitriptyline in patients with
anorexia nervosa, Biederman et al22 found
no association between plasma levels of
the drug and improvement in weight and/
or psychological symptoms. Because of the
significant side effect burden associated
with these agents, patients would often
discontinue treatment early, thus leading to
a drastic decrease in their use, even in the
psychiatric community. Some of these
adverse effects include hypotension,
arrhythmias, tachycardia, fatigue, confusion, constipation, hyperglycemia,
increased liver enzymes, blurred vision,
and anticholinergic effects.22
Mirtazapine (a tetracyclic antipsychotic)
and olanzapine (an atypical antipsychotic)
have also been used as appetite stimulants. Mirtazapine works via its central
presynaptic alpha2-adrenergic antagonist
effects, resulting in an increased release
of norepinephrine and serotonin. It is also
a potent antagonist of 5-HT2 and 5-HT3
serotonin receptors. Olanzapine displays
significant antagonism of serotonin 5-HT2A
and 5-HT2C, dopamine, histamine H1, and
alpha1-adrenergic receptors, but shows
moderate antagonism of 5-HT3 receptors.
Although mirtazapine and olanzapine are
not selective in their antagonism, it has
been postulated that they may still be
efficacious. The binding affinity for the
5-HT3 receptor in both these drugs seems
to be similar to that of the more selective
agents.23 Both medications have some
clinical evidence to support their use
as adjunctive agents in oncology and
cachexia treatment regimens. Several
case studies have supported the use of
olanzapine in patients with anorexia
nervosa to stimulate weight gain.24,25
Critics may suggest that the psychiatric
effects of these agents is what is responsible for these changes, given that a
patient who “feels” better will be more
inclined to eat.25 Studies have reported
weight gain of up to 10 kg over 1 year in
patients receiving olanzapine treatment.26
Additional side effects seen with these
agents include somnolence, hyperlipidemia, xerostomia, dizziness, dyspepsia,
and weakness.
Cyproheptadine is a histamine and
serotonin antagonist that competes with
histamine for the H1-receptor site on
effector cells in the gastrointestinal
tract, blood vessels, and respiratory
tract. This drug has been extensively
used for appetite stimulation in patients
aged 13 years and older with anorexia
nervosa. Because of its favorable effects
in this area, it has also been studied in
the cachexia population. In a large,
placebo-controlled study in patients with
advanced cancer, a dose of 8 mg 3 times
daily did prove to have a mild stimulatory effect on appetite but failed to
prevent weight loss.27 It has, however,
been proven to be effective in patients
with carcinoid syndrome and associated
anorexia/cachexia. It is thought that in
these patients the counteractive effects of
increased serotonin activity may be the
mechanism of action.28 Although no
major side effects have been seen, this
medication has fallen out of favor as an
antihistamine with the development of
other less sedating agents. Side effects
include tachycardia, sedation, seizures,
fatigue, headache, rash, anemia, and
photosensitivity. It is unclear whether it is
safe to use this drug in infants and young
children, so caution is advised.
Hydrazine sulfate is an inhibitor of
phosphoenolpyruvate kinase, an
enzyme involved in reconstruction of
glucose from anaerobically metabolized
lactic acid. It was thought that by
interrupting gluconeogenesis, the
mechanism behind cancer cachexia
would be affected beneficially. It is
difficult to determine whether this agent
would be beneficial in other populations
as it appears to have been exclusively
studied in the oncology population and
may work on a specific physiological
mechanism induced by the illness.
However, after 3 different placebocontrolled trials, it does not appear that
this agent benefits even cancer patients
with regard to progression of cachexia or
weight gain.29-31 In addition to failing to
show benefit, hydrazine sulfate has been
associated with several cases of central
and peripheral neurotoxicity and fatal
cases of hepatorenal failure. For these
reasons, this agent is not recommended
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for use for appetite stimulation, especially
in the pediatric population.
Extensive amounts of literature support
the role of serotonin antagonism in normal
feeding behaviors.32 Krause et al33
demonstrated elevated levels of plasmafree tryptophan, along with increased CNS
levels of 5HIAA (a serotonin metabolite),
in several tumor-bearing rats exhibiting
signs of cachexia.33 Based on this finding,
serotonin antagonists have been investigated for their use as adjunctive appetite
stimulants. It is unclear as to which
subtype of 5HT receptors are involved in
appetite; however, some studies have
shown that the 5HT3 receptors are the
most critical.34 Ondansetron is a 5HT3
receptor antagonist that is commonly
used as an antiemetic agent in patients
undergoing chemotherapy. In one study
in cancer cachexia patients using
ondansetron, a dose of 8 mg twice daily
was shown to improve the ability of
patients to enjoy food but did not prevent
weight loss in this population.35 Although
this agent may not have demonstrated
efficacy in preventing weight loss, it has
been proven useful to ameliorate nausea
and vomiting in patients undergoing
extensive treatment and may therefore
help patients tolerate food better.
Ondansetron may be useful as an
adjunctive agent in trying to promote
weight gain. Side effects are fairly benign
and may include tachycardia, hypotension,
flushing, lightheadedness, headache,
fatigue, constipation, or blurred vision.
Metoclopramide is a potent dopamine
receptor antagonist. It blocks dopamine
receptors in the chemoreceptor trigger
zone within the CNS, thereby preventing
emesis, and also increases gastric motility
to potentially decrease nausea and
increase appetite. Metoclopramide has
been shown to be effective in preventing
chemotherapy-induced nausea and
vomiting.36 Studies have shown no
correlation between serum levels of the
drug and its effects, so typical antimotility
doses can be used. In a placebocontrolled crossover trial, metoclopramide
resulted in a significant decrease in
nausea but did not improve caloric intake
or weight gain. There have been no
specific studies done in the pediatric
vol. 2 • no. 6
population because of the risk of
extrapyramidal side effects, some of
which may be irreversible.37 The drug
comes with an FDA-issued black box
warning for tardive dyskinesia, and thus
many practitioners tend to avoid its use in
children. Other side effects include
fatigue, anxiety, hallucinations, dystonia,
gynecomastia, diarrhea, and jaundice.
Hormonal Therapy
Megestrol acetate is commonly used in
female patients for treatment of metastatic
breast cancer or endometrial cancer. An
unfavorable side effect is the weight gain
associated with this agent, which led to
the investigation of its use as an appetite
stimulant. Loprinzi et al38 completed a
phase III evaluation using 4 different
doses for cancer anorexia and cachexia,
ranging from 160 to 1280 mg daily. From
this evaluation it was found that there is a
positive correlation between the dose and
its effect, where higher doses were
associated with more nonfluid weight
gain. In another study by Loprinzi et al,6
the efficacy of megestrol acetate was
compared with dexamethasone and
fluoxymesterone (an anabolic steroid with
strong androgenic properties) in treating
cachexia. It was found that megestrol
acetate and dexamethasone both have a
better appetite stimulation profile than
fluoxymesterone and that dexamethasone
had a higher rate of discontinuation
because of its corticosteroid side effects.
Side effects reported with megestrol
acetate use include mild edema and an
increased risk of venous thromboembolism (especially with concomitant
chemotherapy). These studies used the
tablet form of the drug, but oral suspension has been shown to correlate with
better compliance, lower expense, and
possibly better bioavailability.
Growth Factors/
Hormone-Like Factors
Ghrelin is a peptide hormone that is
produced by the stomach. It signals the
hypothalamus to stimulate the release
of growth hormone from the anterior
ICAN: Infant, Child, & Adolescent Nutrition
pituitary. By administering supplemental
ghrelin, it replicates postprandial blood
concentrations and therefore should
increase the sensation of hunger and
overall food intake. Gullett et al39
reviewed several trials involving the use of
synthetic ghrelin or ghrelin receptor
agonists for weight gain. All these trials
showed a positive result, which was a
marked increase in food intake resulting
in an increase in weight. No adverse
events were reported. As this is a
hormone that is normally produced by the
body in association with the regulation of
fasting, its mechanism is well known in its
role as an appetite stimulant. However,
also related to this particular mechanism,
it could be used by the cancerous tumors
in cancer patients and cause further tumor
growth. More trials should be done before
this therapy can be recommended.
One of the metabolic changes seen in
the body, when experiencing anorexia
and cachexia, is insulin resistance. Insulin
is an important hormone as it relates to
appetite regulation and growth. In one
Swedish study, Lundholm et al40 found
that insulin dosed at 0.11 units/kg/d
with either breakfast or lunch can
stimulate significant carbohydrate intake
and increase whole body fat. This study
also showed that insulin provided the
best palliative care for weight gain across
the board regardless of the patients’
various different diagnoses. Side effects
for treating with insulin include risk for
hypoglycemia, especially when given
without food.
Tumor Necrosis Factor
(TNF) Inhibition
Anorexia and loss of body weight are
associated with reduced muscle mass and
adipose tissue, accompanied by increases
in muscle protein breakdown and
lipolysis. These changes have been
shown to be due in part to an inflammatory response with the help of specific
cytokines, including TNF. Therefore,
therapeutic strategies that target TNF have
been explored in appetite stimulation.
Pentoxifylline, a methylxanthine
derivative approved for use in intermittent
claudication, inhibits TNF production by
monocytes and T lymphocytes in vitro.
One study showed that pentoxifylline
downregulated TNF expression in cancer
patients at a dose of 400 mg 3 times
daily41; however, a placebo-controlled
study showed no benefit in improving
appetite or weight gain in patients
exhibiting cachetic/anorexic symptoms.42
Side effects with this agent are usually
mild and may include hypotension,
angina, headache, dizziness, dyspepsia,
nausea, or blurred vision.
Etanercept is a monoclonal antibody
that binds to TNF and blocks its interaction with cell surface TNF receptors
making TNF biologically inactive. It can
modulate physiological responses that are
generally induced or regulated by TNF.
One small trial demonstrated the
reduction of fatigue and increased
tolerability of chemotherapy with
etanercept; however, no evidence on
appetite stimulation or weight gain was
noted.43 Etanercept should be avoided in
all children and adolescents unless
absolutely necessary because of the
increased risk of lymphomas and
leukemia. It is typically used at a dose of
25 mg subcutaneously twice weekly and
has several notable side effects. These
include flushing, peripheral edema,
pancytopenia, dizziness, fever, rash,
and increased risk for infections.
Infliximab is a chimeric IgG1-kappa
monoclonal antibody that is typically used
in rheumatoid arthritis and Crohn disease
and has been incorporated into several
chemotherapy regimens. Its role as a TNF
inhibitor may contribute to reversing the
muscle wasting of cachexia and anorexia.
Jatoi et al44 looked at the effect of
infliximab in the elderly population as
well as in patients with non-small-cell lung
cancer. Some side effects noted were
dyspnea, fatigue, hypotension, hypoxia,
cardiac ischemia and infarction, thrombosis, melena, and muscle weakness. The
trial was stopped early because of the
increase of fatigue in the infliximab and
docetaxel study arm. None of the patients
in the trial reached the study endpoint of
positive 10% weight gain. Moreover, there
was no significant difference between the
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ICAN: Infant, Child, & Adolescent Nutrition
results of the 2 arms, and its use was
associated with a worsening in quality
of life for the majority of patients. It is
possible that the negative findings can be
attributed to the low infliximab dose used
in this study, which may not have allowed
for maximum potential efficacy in this
population.44 Without additional studies
with demonstrated positive outcomes, its
use as an appetite stimulant cannot be
recommended at this time.
Another potent TNF inhibitor is
thalidomide, which is an inhibitor of TNF
synthesis. Gordon et al45 studied the effect
of thalidomide in pancreatic cancer
patients. The results were significant in
that weight gain occurred in patients
taking thalidomide when compared with
the weight loss in the placebo group.
There was also another open label pilot
study of thalidomide use as treatment for
cachexia in inoperable esophageal cancer
patients, which was found to reverse
weight loss as well as increase lean body
mass.46 There were several patients who
were withdrawn from the study because
of significant side effects including
peripheral neuropathy, rash, and severe
daytime somnolence. Thalidomide is also
known to cause fetal malformation, and
in order for premenopausal female
patients to take this medication they are
required to use at least 2 methods of birth
control and undergo routine pregnancy
testing before and during treatment.
Complementary and
Alternative Medicine
It is important to consider the several
nutritional and alternative therapies
that have been investigated as appetite
stimulants. Eicosapentaenoic acid (EPA)
is a long-chained polyunsaturated fatty
acid found in the omega-3 fish oil
supplement along with docosahexaenoic
acid and vitamin E. In mice, it was found
that the combination inhibited tumorinduced lipolysis and muscle degradation, probably by suppressing cytokine
interleukin-6 and by decreasing the
presence of a tumor-specific factor.47
There have been an array of smaller
studies using a variety of dosages and
inconsistent study designs that showed
positive results with the use of EPA. A
review by Dewey et al47 analyzed and
assessed the randomized controlled trials
involving EPA in the treatment arm in
comparison with placebo or with another
control. There was an overall lack of
efficacy seen when analyzing all the
trials, although because of the various
study designs and doses used it was
difficult to compare them all with one
another. The most commonly noted side
effect was gastrointestinal symptoms (eg,
abdominal discomfort, diarrhea, nausea,
and vomiting). The authors concluded
there was insufficient data to define an
optimal dose of EPA. Ideally, better
designed, large-scale, randomized
controlled trials comparing EPA to
placebo in different populations are
needed to derive a definite conclusion.
Melatonin is a pineal hormone that
regulates the circadian rhythm within the
body thereby affecting sleep cycles and
may help regulate the neuroendocrine
system. Lissoni et al48 investigated the use
of melatonin on serum TNF levels and
suggested it may play a role in treating
cachexia. One hundred nontreatable
metastatic solid tumor patients were
enrolled in this study and were randomized to receive either supportive care
alone or supportive care with a bedtime
dose of melatonin. The authors found
significant evidence that melatonin was
able to attenuate weight loss when
compared with supportive care alone and
demonstrated that the mean TNF
concentration in the melatonin group
decreased significantly. This positive
result showed that by lowering levels of
TNF-α along with good weight attenuation, melatonin may be an efficacious
appetite stimulant in both anorexic and
cachectic patients. Given that melatonin
is used as a sleep aid in the pediatric
population, and despite the lack of
evidence-based data as an appetite
stimulant in this age-group, these findings
suggest that melatonin may be a viable
option for children and adolescents
although additional research is still
needed to determine optimal dosing.
Practitioners should also remember that
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this supplement is not an FDA-approved
medication and potency may vary among
manufacturers and even between lots
from the same manufacturer.
Ginger (Zingiber officinalis) is an agent
that has been extensively used for
gastrointestinal disturbances, such as
dyspepsia, flatulence, abdominal
discomfort, and diarrhea. Ancient
Chinese, Japanese, and Indian medicine
have all used ginger as a digestive aid. It
is also often used to treat motion sickness
and for the prevention and amelioration
of morning sickness.49 The mechanism for
its therapeutic effect is unknown, but Wu
et al50 did report that ginger can lower the
time of gastric emptying and increase
motility in healthy patients. Similarly,
Hveem et al51 showed that with this
increased gastric emptying, postprandial
hunger would increase and gut fullness
would decrease. This suggests that the
use of ginger may increase hunger and
food intake, thereby combating the
wasting issues seen in anorexia and
cachexia. The amount of ginger used in
this study was 1200 mg ginger root
powder, filled into 3 capsules, and
administered an hour before food was
provided. Pediatric-specific dosing is still
lacking although adolescent patients
could safely use the 1200-mg dose.
Other Factors: Taste
Disturbances
In patients exhibiting unexplained
weight loss and loss of appetite, it is
prudent to review their medication profile
in order to identify possible medications
that may be suppressing appetite or causing
known taste disturbances (Table 2).
Common culprits for taste disturbances
are antimicrobials, such as clindamycin,
doxycycline, fluconazole, and metronidazole. The antihypertensive agent captopril
is also associated with alterations in taste.
Parenteral nutrition use may also cause
taste disturbances, in particular intravenous fat emulsions, which may alter taste
and satiety.52 By recognizing these
potential effects, practitioners can
consider therapeutic alternatives and
adjust treatments accordingly.
vol. 2 • no. 6
ICAN: Infant, Child, & Adolescent Nutrition
Summary
Table 2.
Drugs That Affect Appetite
Drugs That Decrease Appetite
Drugs That Stimulate Appetite
Aluminum hydroxide
Benzodiazepines
Amphetamines
Clemastine
Cisplatin
Cyproheptadine HCl
Cholestyramine
Dronabinol
Dactinomycin
Glucocorticoids
Digoxin
Insulin
Ethambutol
Lithium
Furosemide
Megestrol acetate
Griseofulvin
Oral contraceptives
Hydralazine
Phenothiazines
Hydroxychloroquine
Tricyclic antidepressants
Hydroxyurea
Itraconazole
Lamivudine
Methenamine
Methotrexate
Although many agents have been
evaluated for their use as appetite
stimulants, the majority of the studies
have focused specifically on cancerassociated cachexia/anorexia. Because of
the increasing evidence suggesting that
specific physiological processes are
responsible for this syndrome, some of
the aforementioned therapies may not be
effective for use in patients outside of
the specific cancer population. Results
also may not be applicable for use in
pediatric and adolescent patients
because of the lack of studies in this
population. However, practitioners may
use the evidence available to gauge the
appropriateness of therapy for appetite
stimulation and may apply the results
from these studies to their own clinical
situations. To date only corticosteroids
and progestational agents have been
extensively proven to be statistically
beneficial in promoting appetite and
weight gain, although several other
agents may be useful as well. As
previously noted, larger, more generalized studies would be extremely useful
to confirm the effectiveness of specific
agents. The lack of pediatric-specific
dosing continues to make the use of
these agents challenging at best.
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Sibutramine
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