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The Pathophysiology of Chemotherapy-Induced Nausea and

Vomiting

Article in Gastroenterology Nursing · November 2005

DOI: 10.1097/00001610-200511000-00003 · Source: PubMed

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The Pathophysiology of
Chemotherapy-Induced
Nausea and Vomiting
Paul D. Baker, MSN, RN
Sandra L. Morzorati, PhD
Marsha L. Ellett, DNS, RN, CGRN

Chemotherapy-induced nausea and vomiting is a major debilitating side effect of oncology treatment despite
recent advances in pharmaceutical management. Nurses who provide care to patients experiencing nausea
and vomiting are often only marginally aware of the pathophysiological processes involved in the treatment.
A better understanding of the science behind current interventions to reduce nausea and vomiting may
help nurses use those interventions more effectively. This article reviews current knowledge about the
pathophysiology of chemotherapy-induced nausea and vomiting. By understanding the pathophysiology behind
this patient experience, gastroenterology nurses can develop a better understanding of the common symptoms
of nausea and vomiting in general. When a nurse understands the complexity of factors causing nausea and
vomiting, he or she will be better able to provide appropriate interventions to reduce these symptoms.

C
hemotherapy-induced nausea and vomiting
(CINV) is a major debilitating side effect of on-
cology treatment despite recent advances in the
pharmaceutical treatment of nausea and vomit-
ing. In the past, patients ranked nausea and vomiting as the
top two most difficult side effects of chemotherapy treatment.
Today studies show nausea is still considered the worst side
effect, with vomiting ranking from third to fifth (Wickham,
2003). As a result, patients may conclude that alterations in
their quality of life from nausea and vomiting overshadow
the need to remain compliant with their cancer treatment.
Nurses who provide care to patients experiencing nausea
and vomiting are often only marginally aware of the patho-
physiological processes involved in the treatment. Yet nurses
are often directly involved in how antiemetic interventions are
Received April 16, 2005; accepted May 25, 2005.
About the authors: Paul D. Baker, MSN, RN, is Staff Nurse in the Pediatric
Intensive Care Unit, Riley Hospital for Children, Indianapolis, Indiana, and
Clinical Instructor, Ball State University School of Nursing, Muncie, Indiana.
Sandra L. Morzorati, PhD, is Associate Research Professor; and Marsha L.
Ellett, DNS, RN, CGRN, is Associate Professor; Indiana University School
of Nursing, Indianapolis.
Correspondence to: Paul D. Baker, MSN, RN, Riley Hospital for Children,
720 Barnhill Drive, Indianapolis, IN 46220 (e-mail: pdbnurse@comcast.net).
implemented (Fromer, 2005). A better understanding of the
science behind current interventions to reduce nausea and
vomiting might help nurses use those interventions more effec-
tively. More effective relief of the symptoms of nausea and
vomiting can in turn lead to better compliance with treatments
and, possibly, lessen morbidity and mortality in patients.
This article reviews the current understanding of the patho-
physiology of CINV. By understanding the pathophysiology,
gastroenterology nurses can develop a better understanding
of the common symptoms of nausea and vomiting. The dis-
cussion begins with the definitions of nausea, vomiting, and
retching, followed by a discussion of the mechanism of vom-
iting, the various anatomical structures involved in CINV, and
how these work together. The article concludes with a discus-
sion of the complications of CINV and presentation of useful
classification schemes related to the pharmaceutical manage-
ment of nausea and vomiting.
Terminology
Definitions
Nausea and vomiting actually refer to three different con-
cepts: nausea, vomiting, and retching. Nausea is defined as the
“subjectively unpleasant sensation associated with flushing,

469
3214-03_GN280604_Baker.qxd 12/9/05 4:04 PM Page 470
tachycardia, and an awareness of the urge to vomit” (Ameri-
can Society of Health-System Pharmacists [ASHP], 1999,
p. 729). The experience of nausea is a subjective determina-
tion by the patient because there generally is no obvious out-
ward sign of the sensation by the patient until vomiting occurs
(Purl & Wickham, 2002). Physical symptoms associated with
nausea are increased salivation, swallowing, and tachycardia
(Hogan & Grant, 1997).
Vomiting is “characterized by contraction of the abdom-
inal muscles, descent of the diaphragm, and opening of the
gastric cardia, resulting in expulsion of stomach contents
from the mouth” (ASHP, 1999, p. 729). Because vomiting
can be quantified by frequency of occurrence and by the vol-
ume of emesis, it is a more objective measure than nausea
(Purl & Wickham, 2002).
Retching “involves spasmodic contractions of the
diaphragm, thoracic, and abdominal wall muscles without
expulsion of gastric contents” (ASHP, 1999, p. 729). Retch-
ing is often not assessed and frequently not present as part
of nausea and vomiting symptoms even though it may be
an important element for certain patients and in particular
chemotherapy regimens (Morrow, 1984; Rhodes &
McDaniel, 1999).
Phases of Nausea and Vomiting
There are three phases of vomiting associated with chemo-
therapy, all of which apply equally to nausea. Acute vomit-
ing is the direct response to initial administration of
chemotherapy. Acute vomiting is traditionally referred to as
any emetic episode occurring within the first 16 to 24 hours
after administering the chemotherapy (ASHP, 1999). Vomit-
ing that occurs after the acute period is generally referred to
as delayed vomiting and can last as long as 6 or 7 days
(ASHP). Anticipatory vomiting is a learned or conditioned
response. It generally occurs before symptoms of nausea and
vomiting would be expected and is the result of cognitive
associations with previous negative experiences of nausea
and vomiting (ASHP).
Mechanisms of Nausea and Vomiting
The existence of a vomiting center (VC) was initially con-
firmed by Borison and Wang (1953). The VC is the portion
of the brain responsible for collecting emetogenic stimuli
from throughout the body and coordinating the develop-
ment of nausea and vomiting. Individual differences in
response to emetogenic stimuli can be explained by consid-
ering that each individual may require a different degree of
stimulation to the VC to reach the threshold of nausea or
vomiting (Hockenberry-Eaton & Benner, 1990).
Nausea
Nausea is the most difficult symptom to quantify, mainly
because of its subjective nature. It can be difficult to describe
to a patient what to expect, especially if he or she is naïve to
nausea, has cultural differences related to the concept of nau-
sea, or has decreased cognitive abilities because of age or dis-
ability (Leslie & Reynolds, 1993; Veyrat-Follet, Farinotti, &
Palmer, 1997).
Although it is generally assumed that nausea is a symp-
tom of emetogenic stimuli not significant enough to cause
470
vomiting, there is little experimental evidence for this; how-
ever, treatment for vomiting is usually effective for nausea
(Andrews, Rapeport, & Sanger, 1988). All references to the
causation and treatment of vomiting discussed in the remain-
der of this article, therefore, can be assumed to also apply to
nausea unless otherwise stated.
Physiological symptoms of nausea can include cold sweat-
ing, flushed skin, intercostal dilation, tachycardia, and hyper-
salivation (Leslie & Reynolds, 1993; Veyrat-Follet et al.,
1997). These symptoms indicate autonomic nervous system
(ANS) involvement in the nausea process (Morrow, Roscoe,
Hickok, Andrews, & Matteson, 2002). When a patient is
nauseated, the gastrointestinal (GI) tract is undergoing
changes to prevent the digestion and absorption of any
noxious substances that have been ingested. The GI tract
slows down and begins to prepare itself for an emetic
action (Naylor & Rudd, 1996).
Retching
Retching is a rhythmic contraction of the diaphragm, the
rectus abdominis, and the external intercostals muscles. The
internal intercostal muscles also contract, but this occurs
“out of phase” with the others. The net effect is a decreased
intrathoracic pressure and an increased intra-abdominal
pressure (Leslie & Reynolds, 1993). Retching does not,
however, relieve the subjective feelings of nausea (Hogan &
Grant, 1997). Three possible purposes for retching are: (a)
to overcome the upper GI reflux barrier by relaxing the
lower esophageal sphincter, (b) to sample the contents of
the stomach to see how fluid they are, and (c) to “wind up”
the neural circuitry that creates an emetic episode (Leslie &
Reynolds).
Vomiting
The purpose of vomiting is to expel noxious contents from
the GI tract. Once the individual is exposed to enough ini-
tial stimuli to the VC, the usual sequence of events begins
with nausea. This is followed by retching, then by vomiting,
although retching is frequently absent from the sequence.
Nausea does not always lead to vomiting, and patients can
vomit without ever experiencing the sensation of nausea.
There appears, therefore, to be individual and situational
variations associated with the sequence of events leading to
vomiting (Leslie & Reynolds, 1993).
There are three phases to vomiting (Table 1). The first
phase is the pre-ejection or prodromal phase. This phase is
often accompanied by nausea and sometimes retching. The
GI tract prepares itself for an emetic episode. The second
phase is the ejection phase or the actual expulsion of stomach
contents. The final phase is the postejection phase. Vomiting
has stopped, nausea dissipates, and the individual generally
feels better. Figure 1 illustrates the physical mechanisms that
create an emetic episode.
Anatomical Structures Related to
Chemotherapy-Induced Nausea
and Vomiting
Vomiting Center
The VC is the primary structure for coordinating nausea and
vomiting (Leslie & Reynolds, 1993). Rather than being in a
specific location, the VC is a collection of neurons distrib-
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T A B L E 1

The Three Phases of Vomiting

Term Description

Prodromal The vomiting center (VC) sends out motor stimuli to the GI tract to prepare it for emesis. Vagal efferents
stimulate the proximal stomach to relax, mediated, in part, by the neurotransmitter vasoactive intestinal
polypeptide (VIP) (Vayrat-Follet, Farinotti, & Palmer, 1997). The VC also initiates a retrograde giant con-
traction (RGC) in the small intestine to move the contents of the upper small intestine up into the stom-
ach. This serves to move any contaminated contents up into the stomach to be ejected and also helps
lower the acidity of the stomach contents to prevent damage to the upper GI tract during vomiting. These
events must occur before vomiting can occur. Any contents in the lower small intestine are moved down
into the colon (Vayrate-Follet, Farinotti, & Palmer).
Ejection The actual expulsion of stomach contents. There is a coordinated contraction of the diaphragm, rectus
abdominis, and external intercostal muscles, although the rectus abdominis contraction is longer and
more intense in vomiting than in retching. The internal intercostal muscles do not contract, and the
periesophageal diaphragm relaxes. The net result is a compression of the stomach from the bottom up,
leading to the ejection of stomach contents (Leslie & Reynolds, 1993). Increased salivation helps provide
an alkaline buffer in the mouth against acidic stomach contents (Freeman, Bountra, Dale, Gardner, &
Twissell, 1993).
Post-ejection Vomiting has stopped, nausea dissipates, and the individual generally feels better. The assumed purpose
of feeling better is to make sure that the actual act of vomiting and the resulting ejection of noxious con-
tents is not an aversive experience (Leslie & Reynolds, 1993).

uted within the medulla oblongata (ASHP, 1999). Several
different neurotransmitters have been associated with neural
signals to the VC (Hogan & Grant, 1997), including sero-
tonin, dopamine, histamine, acetylcholine, and substance-P
(ASHP) (Table 2). Of these neurotransmitters, serotonin
and substance-P are considered the primary mediators, and
dopamine a secondary mediator, of nausea and vomiting
induction (Dupuis & Nathan, 2003). Figure 2 illustrates the
various inputs into the VC and how they relate to each other.
Chemoreceptor Trigger Zone
The identity and location of the chemoreceptor trigger zone
(CTZ) were confirmed in the 1950s (Borison & Wang, 1953).
The CTZ is a specific location in the brain directly sensitive
to chemical agents with known emetogenic potential. The
location of the CTZ in the brain has been identified within
the area postrema (AP) region on the bottom edge of the
fourth ventricle (Leslie & Reynolds, 1993) (Figure 3). The AP
is described in additional detail in this section.
Vagus Nerve
The vagus (vagal) nerve is an important source of stimuli
to the CTZ and to the VC with regard to emetogenic
potential. The vagus nerve receives sensory information from
organs of the abdomen, including the GI tract. The gut wall
contains mechanoreceptors to detect overdistention of the
gut and chemoreceptors to detect abnormal stimuli, such as
acidity, alkalinity, hypertonic fluids, temperature extremes,
and irritants. Enterochromaffin (EC) cells in the gut respond
to toxic substances within the contents of the gut or in the
blood perfusing the gut (Leslie & Reynolds, 1993).
Enterochromaffin cells located in the GI tract are primarily
responsible for the emetogenic potential of most chemother-
apy agents. Active metabolites of chemotherapy agents pass
through the bloodstream to the GI tract, where they directly
cause damage to the EC cells (Andrews, Naylor, & Joss,
1998), possibly by the generation of free radicals (Rudd
& Andrews, 2005). This damage leads to the release of the
neurotransmitter serotonin (5-hydroxy tryptamine, or 5-HT)
from the EC cells, which stimulates the vagus nerve via 5-HT3
receptors (Leslie & Reynolds, 1993). Venous blood from the
GI tract passes through the liver via the hepatic portal vein,
which is also innervated by the vagus. Metabolites from the
GI tract could directly affect the liver to send its own neuro-
logical signals via the vagus to the CTZ (Freeman, Bountra,
Dale, Gardner, & Twissell, 1993).
The vagus nerve is the primary afferent nerve of the GI
tract. Most of the messages from the gut transmitted via the
vagus nerve involve the neurotransmitter serotonin. In fact,
80% of serotonin in the body is located in EC cells (Veyrat-
Follet et al., 1997). These cells mediate messages to the brain
via the vagus nerve to the nucleus tractus solitarius (NTS)
(Naylor & Rudd, 1996). Messages from the EC cells can
also activate reflexes in the gut to regulate secretion of diges-
tive enzymes and peristalsis. Serotonin, along with several
tachykinins, can have direct local physiological effects, such
as smooth muscle relaxation, vasodilation, and secretion of
water and electrolytes (Ahlman & Nilsson, 2001).
Because serotonin mediates messages about normal phys-
iological and pathophysiological stimuli from the gut to the
brain, there must be something specific about the signal sent
by the EC cells in response to cytotoxic drugs. That signal is
believed to be a unique “pattern and intensity” of stimulation
at the vagus nerve to the dorsal motor nucleus of the vagus
(DMV) and the NTS (Leslie & Reynolds, 1993; Rudd &
Andrews, 2005). The support for the thesis that the primary
emetogenic stimulus comes from the EC cells is the success of
the drugs referred to as 5-HT3 receptor antagonists in reduc-
ing and preventing CINV. Their ability to block 5-HT3 recep-
tors in the gut and in the NTS and CTZ revolutionized our

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3214-03_GN280604_Baker.qxd 12/9/05 4:04 PM Page 472
ability to reduce CINV. Additional support was provided
with the measurement of 5-hydroxy-indoleacetic acid (5-
HIAA) as a urinary metabolite of serotonin. The elevation of
5-HIAA in the urine correlates to the onset and increased
intensity of acute nausea and vomiting (Wickham, 2003).
Nucleus Tractus Solitarius
The nucleus tractus solitarius (NTS) is considered the main
site for the termination of vagal afferents from the gut. It lies
directly adjacent to both the DMV and to the AP that con-
tains the CTZ (Andrews & Davis, 1993; Leslie & Reynolds,
1993), as shown in Figure 3. A portion of the NTS that lies
directly against the AP is the subnucleus gelantinosus. The
cell structures of the subnucleus gelantinosus and the AP are
virtually identical, indicating the possibility that the CTZ
472
F I G U R E 1 . The main inputs
into the vomiting center and the
motor outputs that lead to vomiting.
evolved from the subnucleus gelantinosus after migrating
below the blood-brain barrier (Leslie & Reynolds). Emeto-
genic stimuli from the EC cells in the gut are transmitted via
5-HT3 receptors on vagal fibers to the DMV and NTS (Leslie
& Reynolds). Substance-P released in the NTS activates NK-
1 receptors in the NTS to pass the signal on to the CTZ, and
then to the VC (Diemunsch & Grelot, 2000).
Dorsal Motor Nucleus of the Vagus
The dorsal motor nucleus of the vagus (DMV) is the part of
the brain where motor efferent signals from the brain to the
abdomen originate. Neural signals via the DMV to the gut,
diaphragm, and abdominal muscles prepare the body for
emesis, and later coordinate the physical act of vomiting
(Stahl, 2003).
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T A B L E 2

Neurotransmitters of Nausea and Vomiting

Neurotransmitter Description

Serotonin Primary mediator of neural signals from the gut (EC cells) to the NTS. Activates 5HT3 receptors on
vagal afferents in the gut and the NTS to induce nausea and vomiting (Naylor & Rudd, 1996). Med-
ications referred to as 5HT3 receptor antagonists (e.g., ondansetron, granisetron, palanosetron)
reduce nausea and vomiting by blocking serotonin from binding to these receptors.
Substance-P Activates NK-1 receptors, primarily found in the NTS and DMV, that transmit signals from the vagus
nerve to the CTZ to induce nausea and vomiting (Diemunsch & Grelot, 2000). Medications referred
to as NK-1 receptor antagonists (e.g., aprepitant) reduce nausea and vomiting by blocking sub-
stance P from binding to these receptors.
Dopamine Its role in nausea and vomiting is unclear. Dopamine receptor antagonists (e.g., promethazine,
metoclopromide) have been used somewhat successfully in the past to treat CINV. Their effective-
ness may be related to their anti-dyspeptic effects (Rudd & Andrews, 2005)

Area Postrema
The AP is a U-shaped structure located on the caudal side of
the fourth ventricle (Leslie & Reynolds, 1993). The CTZ is
located within the AP and is responsible for the transmission
of most of the emetogenic stimuli to the VC. The AP is an
ideal location for CTZ for many reasons. The AP is directly
connected to the NTS and the DMV that receive direct vagal
afferent signals (specifically emetic signals from the EC cells).
The AP is also located outside the selectively permeable blood-
brain barrier while still in contact with cerebrospinal fluid
(CSF). This allows the CTZ to sample the chemical content of
both the CSF and blood from the systemic circulation (Leslie
& Reynolds). In fact, the AP is a richly vascularized section of
the brain (Veyrat-Follet et al., 1997). Thus, the CTZ is well
designed to detect emetogenic substances either centrally via
the bloodstream and CSF or peripherally via nerve impulses.

F I G U R E 2 . The structures
that provide emetogenic stimulus to
the vomiting center. Adapted from
Andrews, P. L. R., & Davis, C. J.
(1993). The mechanism of emesis
induced by anti-cancer therapies. In
P. L. R. Andrews, & G. J. Sanger
(Eds.), Emesis in anti-cancer ther-
apy: Mechanisms and treatment
(p. 135). London: Chapman & Hall
Medical.

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3214-03_GN280604_Baker.qxd 12/9/05 4:04 PM Page 474
If the CTZ does indeed determine its emetogenic stimulus
from sampling the systemic circulation, it is reasonable to
consider there is a “common factor” that accumulates in the
bloodstream in response to chemotherapy agents. This com-
mon factor has yet to be identified, although two suspects are
vasopressin and serotonin (Cubeddu, 1992). It is also possi-
ble the CTZ is able to detect a variety of toxic substances or
endogenous substances released in response to toxins (Naylor
& Rudd, 1996).
Serotonin is highly unlikely as the common factor because
it has a short half-life (Naylor & Rudd) and is rapidly taken
up by platelets in the blood (Leslie & Reynolds, 1993). Ele-
vated plasma levels of vasopressin have been detected in nau-
seated subjects (Andrews et al., 1988; Morrow et al., 2002).
Vasopressin has been implicated as a possible candidate as
part of the mechanism that creates the sensation of nausea,
although studies have shown it does not work alone (Rudd &
Andrews, 2005).
It is considered unlikely that toxins provide a significant
direct stimulus to the CTZ via the systemic circulation. For
one thing, if this were the case, there should be a more rapid
onset of symptoms after administration of chemotherapy
(Leslie & Reynolds, 1993). Instead, CTZ stimulation from
CINV is most likely primarily a result of peripheral stimu-
lation of EC cells in the gut transmitted via vagal nerve
afferents. Vagal afferents may actually extend all the way
into the AP (Leslie & Reynolds, 1993).
Other Factors Affecting CINV
There are a variety of factors that can potentiate CINV. These
factors may help explain the individualistic nature of the
474
F I G U R E 3 . Location of the
dorsal motor vagus nerve, nucleus
of the solitary tract, and chemore-
ceptor trigger zone in the area
postrema of the brain’s fourth ven-
tricle. Adapted from Freeman, A. J.,
Bountra, C., Dale, T. J., Gardner,
C. J., & Twissell, D. J. (1993).
The vomiting reflex and the role
of 5-HT3 receptors. Anti-Cancer
Drugs, 4(Suppl. 2), p. 10. Used with
permission.
nausea and vomiting response. The vestibular apparatus is
involved in the detection of body motion and balance and
has been directly implicated in creating emetogenic stimuli
(Andrews & Davis, 1993). Examples of vestibular stimuli
with emetogenic potential are motion sickness and the
dizziness and nausea associated with inner ear imbalance.
Individuals predisposed to motion sickness have a higher
potential for CINV (Andrews & Davis). Some chemotherapy
agents may directly damage the vestibular afferents, thus
increasing their emetogenic potential (Andrews & Davis).
Other individual characteristics associated with increased
risk for developing CINV are female gender, adults younger
than 50 years, children older than 6 years, anxiety, and low
alcohol intake (Marek, 2003; Schnell, 2003). There is also
growing evidence that small genetic variations can affect
emetogenic potential and response to treatment. One identi-
fied example is associated with the cytochrome P450 (CYP)
enzymes known to metabolize the antiemetic medications
referred to as 5-HT3 receptor antagonists. There is evidence
certain individuals may have CYP 450 enzymes that are
“ultrarapid metabolizers.” These individuals have a much
higher incidence of acute vomiting despite administration
of the 5-HT3 antagonist ondansetron. Granisetron, another
5-HT3 antagonist, is more resistant to these ultrarapid
metabolizers and therefore is a more effective antiemetic
with those individuals (Schnell). Several other genes have
been identified as deserving investigation into possible
implications in determining individual emetogenic responses
(Hesketh, 2004).
A variety of higher brain centers can contribute to stimu-
lation of the VC. Several experiments with direct electrical
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stimulation to a variety of cerebral locations have demon-
strated emetogenic potentials throughout the higher brain
centers (Andrews & Davis, 1993). The limbic system, which
is involved in emotional responses to events or sensory stim-
uli, has also been implicated in a variety of situations directly
inducing vomiting. In general, any situation involving an
intense stimulus or emotional response can contribute to
stimulation of the VC. Some stimuli that can put an already
stimulated VC “over the edge” include taste, smell, pain, and
distress (Andrews & Davis). Table 3 provides a review of
anatomical structures related to CINV.
Two examples of higher brain influences as emetogenic
stimuli are “response expectation” and anticipatory nausea
and vomiting. Response expectation (Morrow, 2003) theo-
rizes that individual emetogenic potential is partially deter-
mined by preconceived expectations. According to Johnson
and Leventhal’s self-regulation theory (Johnson, 1999), an
individual internalizes a structure of expectations (referred to
as schema) based on previous sensory experiences and edu-
cational exercises. When the individual receives a new set of
sensations, he or she attempts to place the new sensations
within the framework, or schema, he or she already has. If
the sensations do not fit the schema, then the individual must
adjust the schema.
With response expectation, the patient may interpret a
new sensation as part of an expected symptom and from that
point on associate that sensation with the symptom, whether
it is related to the symptom or not (Morrow et al., 2002).
Roscoe et al. (2004) noted several reports that demonstrated
a relationship between patient expectations of nausea from
chemotherapy and the development of nausea. Anticipatory
nausea and vomiting is a classical conditioning response that
also involves cerebral pathways (Andrews & Davis, 1993).
Both response expectation and anticipatory nausea and vom-
iting can contribute to the overall emetogenic potential of the
individual undergoing chemotherapy.
Two other influences on emetogenic potential are pharyn-
geal and auricular. The pharyngeal stimulus is also referred to
as the “gag reflex,” in which placing a direct physical stimu-
lus (such as a finger) against the back of the throat can create
a “gag” or retch that can result in vomiting. This stimulus is
transferred to the VC via the glossopharyngeal nerve
(Andrews & Davis, 1993). The auricular stimulus involves
the auricular branch of the vagal nerve that innervates the
tympanum of the ear. Direct stimulation of the tympanum
can also induce immediate emesis (Andrews & Davis).
Another factor that can be considered in the emetogenic
potential of individuals receiving chemotherapy is cortisol
levels (Wickham, 2003). The hypothalamic-pituitary axis is
involved in the regulation of cortisol via the adrenal glands.
CINV has some of the same symptoms as adrenal insuffi-
ciency (which leads to decreased serum cortisol levels), includ-
ing nausea, vomiting, and fatigue (Morrow, 2003; Morrow
et al., 2002). Studies have shown decreased cortisol in the
blood corresponds to increases in the incidence and magni-
tude of CINV. It has been proposed that circadian rhythm
fluctuations in cortisol levels might be used to determine the
most efficacious time to administer chemotherapy to the
patient (Morrow, 2003; Wickham). One possible explanation
for the antiemetic effects of the corticosteroid dexamethasone

T A B L E 3

Anatomical Structures Implicated in Chemotherapy-Induced Nausea and Vomiting

Structure Description

Area postrema (AP) U-shaped structure located in the fourth ventricle that houses the CTZ. The AP is
an ideal location for the CTZ because it can receive signals directly from the
vagus nerve, and also sample the chemical content of both the cerebrospinal
fluid and blood from the systemic circulation.
Chemoreceptor trigger zone (CTZ) A collection of neurons contained in the AP sensitive to chemical agents.
Dorsal motor nucleus of the vagus (DMV) Portion of the brain that transmits motor neural signals to the abdominal organs
via the vagus nerve.
Enterochromaffin (EC) cells Cells in the gut that respond to toxic substances by releasing neurotransmitter-
mediated signals via the vagus nerve.
Higher brain centers Refers to parts of the brain involved in analytical thought. Can contribute to stim-
ulation of the VC, such as an intense somatic experience or emotional response.
Nucleus tractus solitarius (NTS) Termination of sensory information from the vagus nerve, located directly adja-
cent to both the DMV and the CTZ. The NTS transmits information to the CTZ
and the VC.
Vagus (vagal) nerve The primary nerve transmitting sensory information from the abdominal organs,
including the GI tract. The vagus nerve also contains motor fibers to abdominal
organs involved with emesis.
Vestibular apparatus Structures in the ear involved in the detection of body motion and balance that
has been directly implicated in contributing to nausea or vomiting.
Vomiting center (VC) Primary structure for coordinating nausea and vomiting; a collection of neurons
distributed within the medulla oblongata.

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is that it is providing some of the metabolic actions normally
provided by the missing cortisol (Rudd & Andrews, 2005).
Most antiemetic studies have used the chemotherapy agent
cisplatin as the agent of choice because of its high emetogenic
potential but also because of the assumption that most
chemotherapy agents have a similar mechanism of emetogenic
action. Recent studies with cyclophosphamide, an agent clas-
sified as having moderate to high emetogenic potential, have
created a “cyclophosphamide paradox.” Cyclophosphamide
creates an initial CINV experience that is responsive to 5-HT3
antagonists over several days, instead of the 16 to 24 hours
seen with most other emetic agents. This would seem to indi-
cate a prolonged peripheral response on the EC cells of the GI
tract. Yet the level of 5-HIAA metabolite in the urine of
patients receiving cyclophosphamide is relatively normal, sug-
gesting a more central source of the emetic response (Rudd &
Andrews, 2005).
Complications Affecting Nausea
and Vomiting
Nausea and vomiting associated with oncology patients are
not necessarily the result of chemotherapy treatments. Sev-
eral complications of the disease process or other side effects
of chemotherapy can contribute to nausea and vomiting.
Increased intracranial pressure (IICP) is a frequent cause of
nausea and vomiting in patients with cancer, especially in
those with brain tumors (Andrews & Davis, 1993). Brain
tumor growth can crowd the brain inside the cranium to
cause IICP. Cerebral edema can also occur as part of
chemotherapy treatment, either by disruption of the blood-
brain barrier or through electrolyte imbalances (Andrews &
Davis).
Disordered gut function is another common side effect of
chemotherapy. Initial bouts of CINV can lead to delayed gas-
tric emptying and anorexia. Chemotherapy can also cause
direct damage to the rapidly growing cells of the GI mucosal
lining (Andrews & Davis, 1993). For this reason, prokinetic
agents such as metoclopramide (Reglan) may help treat nau-
sea and vomiting by counteracting slow-down of the gut
(Hogan & Grant, 1997). Other complications of chemother-
apy that may interfere with gut function are hepatomegaly
and splenomegaly. Tumor growth or adhesions from surgical
interventions related to cancer treatment can even lead to
bowel obstructions (Hogan & Grant).
Chemotherapy leads to the destruction of large numbers
of cells within the body, causing a buildup of products of cel-
lular breakdown, many of which are toxic to the body and
can contribute to nausea and vomiting symptoms (Andrews
& Davis, 1993). The cellular destruction can lead to small
tears or areas of increased permeability along the GI tract
that may best be treated by dexamethasone and other corti-
costeroids (Andrews & Davis; Hogan & Grant, 1997). Vom-
iting during initial phases of chemotherapy treatment leads to
the loss of water and electrolytes that can cause dehydration
and metabolic disturbances, further complicating the initial
CINV (Andrews & Davis). Chemotherapy can also directly
create metabolic disturbances, such as uremia and hyper-
calcemia (Hogan & Grant).
Other aspects of cancer treatment that can contribute to
nausea and vomiting are anesthesia and pain medications.
Anesthesia is frequently used during the traumatic proce-
476
dures conducted over the course of treatment, including
MRI and bone marrow aspiration (Andrews & Davis,
1993). Pain is a common symptom of cancer and cancer
treatment, and the side effects of many pain medications can
contribute to nausea and vomiting, either through constipa-
tion or the accumulation of their metabolic by-products
(Hogan & Grant, 1997).
Gastroenterology nurses frequently encounter nausea and
vomiting in their practice, usually as a result of anesthesia or
from many of the medications used in gastroenterology
practice. Table 4 provides a list of medications known to
sometimes cause nausea and vomiting. In general, gastro-
enterologists treat nausea and vomiting with the medication
promethazine, switching to ondansetron if vomiting persists
(G. Waltz, personal communication, June 21, 2005).
Phases of Nausea and Vomiting
The mechanisms previously described help explain why
patients experience nausea and vomiting during the acute
phase, which lasts during the first 16 to 24 hours after admin-
istration of chemotherapy. Patients have a high response to 5-
HT3 receptor antagonists during this time, demonstrating
their effectiveness in combating a peripheral-based emeto-
genic stimulus (ASHP, 1999).
After the acute phase, 5-HT3 receptor antagonists rapidly
lose their ability to prevent CINV. This is believed to indicate
a second mechanism is involved as a cause of the onset of
delayed CINV (ASHP, 1999). This is also demonstrated when
measuring the serotonin urinary metabolite 5-HIAA. 5-HIAA
levels no longer correlate with the onset and intensity of
T A B L E 4
Gastroenterology Medications That
May Cause Vomiting
Category Medications
Antacids Calcium carbonate
Anti-diarrheals Atropine, Imodium, Loperamide,
Motofen (Atropine/Difenoxin),
Octreotide
Anti-spasmodics Bentyl (Dicylcomine), Donatal
(Atropine/Hyoscyamine/
Phenobarbital)
Constipation Bisacodyl, Miralax, Lactulose
Enzymes Pancrease
H2 blockers Axid, Cimetidine, Nizatidine, Zantac
Irritable bowel Azathioprine, Azulfidine, Colazal,
disease Dipentum, Immuran, Purinethol,
Remicade, Sulfasalazine
Mouth/throat Mycelex (Clotramazole), Pilocarpine,
Itraconozole
Miscellaneous Ursodiol, Misoprostol, Glycopyrrolate
Information provided by Gail M. Waltz, MSN, RN, CPNP (per-
sonal communication, June 21, 2005).
GASTROENTEROLOGY NURSING
3214-03_GN280604_Baker.qxd 12/16/05 3:14 PM Page 477
delayed CINV symptoms (Wickham, 2003). One possible
explanation for the cause of delayed CINV is that it is the
result of several factors related to the complications of
chemotherapy treatment (Andrews et al., 1998) described
previously. The intensity of delayed CINV symptoms is
directly related to the level of poor control during the acute
phase and to the patient’s anxiety level during treatment
(Rudd & Andrews, 2005).
A new class of antiemetic medication shows promise in
treating both acute and delayed CINV and may provide a
clue to the mechanism of delayed CINV. These medica-
tions, referred to as NK-1 receptor antagonists (Fukunda,
Nakamura, Koga, Furukawa, & Shiroshita, 1999), bind to
the receptor sites of the neurotransmitter substance-P. Studies
have shown NK-1 receptor antagonists bind to substance-P
sites within the NTS to effectively decrease CINV (Fukunda
et al.). When combined with 5-HT3 receptor antagonists,
NK-1 receptor antagonists are more effective in treating acute
nausea and vomiting than 5-HT3 antagonists alone. NK-1
antagonists are also more effective in treating delayed nausea
and vomiting than are 5-HT3 receptor antagonists and
dopamine antagonists (Stahl, 2003).
Multiday chemotherapy regimens are used in many oncol-
ogy treatment protocols. Treating CINV for patients under
these regimens is complicated by the fact that, after the first
day, the patients may be experiencing both acute and delayed
CINV (Mehta, Reed, Kuhlman, Weinstein, & Parsons, 1997).
Anticipatory CINV occurs in approximately 30% of all
chemotherapy patients (Morrow, 2003). Anticipatory CINV
is considered to be a classical conditioning response to poor
experiences with previous chemotherapy sessions. The condi-
tioned responses are stored in the limbic regions of the brain
(ASHP, 1999; King, 1997). Anticipatory CINV usually begins
around the fourth or fifth session (Hockenberry-Eaton &
Benner, 1990), but can occur after just one round of chemo-
VOLUME 28 • NUMBER 6
therapy (Rudd & Andrews, 2005). Once it begins, it is noto-
riously hard to treat (Wickham, 2003).
Conceptual Model of the
Mechanisms of Emetic Effects
Rudd and Andrews (2005) have developed and refined a
graphical conceptual model to represent the variety of mech-
anisms that may contribute to emetic response to chemother-
apy (Figure 4). Bars across the top of the graph represent
when each class of antiemetic medications is most effective.
The 5-HT3 receptor antagonists are most effective during the
first 24 hours after chemotherapy administration, correspon-
ding to the acute phase of nausea and vomiting. Antidyspep-
tic medications, such as metoclopramide, are effective begin-
ning by the end of the first day through the third day by
counteracting the altered GI motility effect of chemotherapy
(Rudd & Andrews).
In a previous version of the model, a prokinetic-sensitive
phase was described in which the patient may discover that
any large or rapid body movement leads to nausea or vom-
iting (Andrews & Davis, 1993). During this phase, patients
want to remain as motionless as possible, usually preferring
to sleep (Purl & Wickham, 2002). NK-1 receptor antago-
nists and glucocorticoids are effective throughout the emetic
response to chemotherapy (Rudd & Andrews).
The model also demonstrates the mechanisms behind the
two main phases of nausea and vomiting. The acute phase is
generally the result of 5-HT release from EC cells in the GI
tract. The delayed phase begins with dyspepsia from altered
gut motility and secretion, and intensifies as inflammatory
reactions and cell breakdown products begin to accumulate
in response to direct cellular damage from the chemotherapy
agents (Rudd & Andrews, 2005).
FIGURE 4 . Conceptual
model of mechanisms involved in
phases of nausea and vomiting.
From Rudd, J. A., & Andrews,
P. L. R. (2005). Chapter 2: Mecha-
nisms of acute, delayed, and
anticipatory emesis induced by
anticancer therapies. In P. J. Hes-
keth (Ed.), Management of nau-
sea and vomiting in cancer and
cancer treatment (p. 33). Sudbury,
MA: Jones and Bartlett Publish-
ers. Available: www.jbpub.com.
Reprinted with permission.
477
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Pharmaceutical Management of
Chemotherapy-Induced Nausea
and Vomiting
T A B L E 5
In the late 1990s, attempts were made by various groups to
develop guidelines for the pharmaceutical management of Emetic Risk of Chemotherapy
nausea and vomiting (ASHP, 1999; Gralla et al., 1999; Multi-
national Association of Supportive Care in Cancer [MASCC], High risk
1998; National Comprehensive Cancer Network [NCCN], Carmustine (> 240 mg/m2) Cisplatin
2001). Follow-up surveys revealed, however, these guidelines Cyclophosphamide Dacarbazine
were frequently not followed and patients were often being (>1500 mg/m2) (> 500 mg/m2)
over- or under-treated (Gralla, 2002; Mertens et al., 2003). Lomustine (>50 mg/m2) Mechlorethamine
Reasons proposed for this include: the guidelines were too
Pentostatin Streptozocin
complex and not readily adaptable to practice (Gralla, 2002);
lack of awareness of the guidelines or confidence in the guide- Dactinomycin
lines; and comfort with previous practice (Mertens et al.). Moderate risk
Adherence to the guidelines was more evident in treating Cyclophosphamide Carmustine
acute nausea and vomiting than in treating delayed nausea (<1500 mg/m2) (<250 mg/m2)
and vomiting (Mertens et al.). Guidelines often did not take Doxorubicin Cisplatin (<50 mg/m2)
into consideration certain individual characteristics that may Epirubicin Cytarabine (> 1 g/m2)
greatly affect drug effectiveness, such as hepatic or renal dys- Idarubicin Irinotecan
function (Goodin & Cunningham, 2002).
Ifosfamide Melphalan
The primary factor to consider in relation to whether a
particular chemotherapy session will lead to nausea or vom- Hexamethylamine Procarbazine
iting is the emetogenic potential of the chemotherapy agent. Carboplatin Mitoxantrone
Hesketh et al. (1997) developed a table ranking chemother- Low risk
apy emetogenic potential into five levels based on the per- Aldesleukin Doxorubicin (<2 mg/m2)
centage of patients who experience emesis when a particular
Methotrexate Fluorouracil
chemotherapy agent is administered. More recently, pub- (>100 mg/m2) (<1000 mg/m2)
lished tables separate chemotherapy agents into the four cat-
Mitoxantrone (<12 mg/m2) Gemcitabine
egories of emetic risk: 1, high; 2, moderate; 3, low; and 4,
minimal (Koeller et al., 2002) (Table 5). Temozolomide Mitomycin
Each group’s guidelines include evidence-based descrip- Etoposide (p.o.) Paclitaxel
tions of pharmaceutical interventions for acute and delayed Asparaginase Thiotepa
nausea and vomiting for various categories of chemotherapy Cytarabine (<1 g/m2) Topotecan
(Koeller et al., 2002). Koeller et al. published a review of Docetaxel
the guidelines and organized a simplified treatment plan
Minimal risk
that summarizes the majority of options available to treat
nausea and vomiting. Methotrexate (<100 mg/m2) Bleomycin
For high-risk chemotherapy, the recommended nausea Capecitabine Rituximab
prophylactic is a 5-HT3 antagonist with a corticosteroid dur- Vincristine Trastuzumab
ing the acute phase (day 1), and either a 5-HT3 antagonist or Vinblastine Vinorelbine
metoclopramide combined with a corticosteroid for the
Etoposide/teniposide
delayed phase (day 2 and later). The moderate category is (intravenous)
treated with a 5-HT3 antagonist on day 1, and during the
delayed phase, one or two of the following: a 5-HT3 antago-
nist, a corticosteroid, or metoclopramide (Koeller et al.).
Low-risk chemotherapy should be treated with a corticos-
teroid or any of the well-known antiemetics. Minimal risk
agents do not require any antiemetic treatment (Koeller et al.) provides improved protection against acute nausea and vom-
Recently a new 5-HT3 antagonist, palonosetron, has been iting, as well as significantly improved protection against
introduced that shows great promise. Palonosetron is espe- delayed nausea and vomiting (Dando & Perry, 2004; de Wit,
cially interesting because of its long half-life and effectiveness 2003; Hesketh et al., 2003; Schnell, 2003). Traditional ther-
in controlling nausea and vomiting as long as 120 hours with apy of a 5-HT3 antagonist with a corticosteroid loses its effi-
one dose (Siddiqui & Scott, 2004). It has been shown to be cacy over multiple rounds of chemotherapy. Adding aprepi-
more effective in treating delayed nausea and vomiting than tant improves antiemetic control that is sustained over
other 5-HT3 antagonists (Fromer, 2005; Siddiqui & Scott). multiple rounds (Dando & Perry; de Wit; de Wit et al., 2003).
With the introduction of aprepitant, the first approved Grunberg (2004) recommended modification to the con-
NK-1 receptor antagonist, healthcare professionals have sensus guideline recommendation of Koeller et al. (2002).
another promising new tool for treating CINV. When added For high emetogenic chemotherapy agents, he suggested
to the current standard of treatment for chemotherapy with adding a NK-1 antagonist during the acute phase, and dur-
high and moderate emetic risk (Stenger, 2004), aprepitant ing the delayed phase, giving a NK-1 antagonist with dex-

478 GASTROENTEROLOGY NURSING

3214-03_GN280604_Baker.qxd 12/16/05 3:14 PM Page 479
amethasone instead of a 5-HT3 antagonist or metoclo-
pramide (Grunberg).
Side effects from aprepitant closely resemble those noted
with 5-HT3 antagonists and include fatigue, anorexia, con-
stipation, diarrhea, nausea, and hiccups (Dando & Perry,
2004). Several drug interactions have been noted, including
those with corticosteroids, midazolam, warfarin, and oral
contraceptives. Corticosteroid doses should be reduced dur-
ing aprepitant administration (Dando & Perry). Patients
taking oral contraceptives should use alternative contracep-
tion while taking aprepitant (Dando & Perry; Olver, 2004).
Currently, aprepitant is offered only in oral form, although
an intravenous version is in clinical trials (Dando & Perry).
Conclusion
Nausea and vomiting associated with cancer is complicated
and multifactorial. Although a goal of chemotherapy treat-
ment should be to prevent CINV, this is not always possible.
Individual variations, complications from the cancer itself,
and behavioral issues of the patient together create an intri-
cate web of factors that determine the patient’s emetogenic
potential to a particular chemotherapy treatment. Other
causes of nausea and vomiting, such as anesthesia, certain
medications, GI illnesses, and increased intracranial pressure,
may have many of the factors described here for CINV.
Recent advances in pharmaceutical management of nausea
and vomiting show great promise in improving outcomes
throughout the patient’s treatment. Some of these new
advances in antiemetic treatment may have application to the
treatment of gastroenterology patients. When a nurse under-
stands the complexity of factors causing nausea and vomit-
ing, he or she will be better able to provide appropriate inter-
ventions to reduce or eliminate the symptoms of nausea and
vomiting.
Acknowledgment
This study was funded by a grant from the Society of Gas-
troenterology Nurses and Associates, Inc.
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