include serotonin, dopamine, and neurokinin 1.

The GI system also plays a large part in the initiation of the

emetic response. The GI tract contains enterochromaffin cells in

the GI mucosa. When these cells are damaged by chemotherapy, radiation, anesthetics, or mechanical irritation, serotonin is

released, which can stimulate the vagal afferents as well as directly

stimulate the VC and NTS. The vomiting center then initiates

the emetic response.

The cerebral cortex and limbic system can stimulate the

emetic center in response to emotional states such as anxiety,

pain, and conditioned responses (anticipatory nausea and vomiting). The neurotransmitters involved in this pathway are less well

understood. Disorders of the vestibular system, such as vertigo

and motion sickness, stimulate the VC through acetylcholine and

histamine release.

DIAGNOSIS

The initial evaluation of the patient with nausea and vomiting

should include the onset of symptoms, the severity and duration of symptoms, hydration status, precipitating factors, current

medical conditions and medications, and food and infectious contacts. The etiology of the nausea and vomiting should be determined, if possible, so that underlying conditions can be treated

specifically. Supportive treatment should be initiated, if needed,

including fluid and electrolyte replacement. If the nausea and

vomiting is mild and self-limited, antiemetic therapy may not be

required. For others, however, the appropriate antiemetic therapy will depend on the patient and the etiology of the nausea

and vomiting.

100 Section 1 General Care

Vagal afferents

Amygdala

5-HT

5-HT3 Receptor

AP and NTS

Central pattern

generator

Vomiting Center

Medulla

Small

intestine

Higher central nervous

system centers

(Chemoreceptor Trigger Zone:

5-HT3, D2 and NK1 receptors)

Vagus nerve

Dorsal vagal complex

Enterochromaffin

cells

CHEMOTHERAPY

FIGURE 6-1 Pathways by which chemotherapeutic agents may produce an emetic response. AP, anterior pituitary; 5-HT, serotonin; 5-HT3,

serotonin type 3 receptor; NTS, nucleus tractus solitarius.

MOTION SICKNESS

Clinical Presentation and Risk Factors

CASE 6-1

QUESTION 1: P.C. is a 27-year-old woman who has no significant medical history, with the exception of moderate

dysmenorrhea and motion sickness associated with travel

by air. Previously, she has taken dimenhydrinate before airplane trips with moderate success. She is engaged to be

married, and she and her fianc ´e have decided on a weeklong

Caribbean cruise for their honeymoon. P.C. is concerned

that she may also develop sea sickness and that dimenhydrinate may not control her symptoms, particularly in the

event of rough weather at sea. Will P.C. be at higher risk for

motion sickness?

The symptoms of motion sickness occur in response to an

unusual perception of real or apparent motion. In these situations, there is sensory conflict about body position or motion

through the visual, vestibular, or body proprioceptors. Acetylcholine is thought to be the primary neurotransmitter involved in

signaling the VC, as is histamine, but to a lesser extent. Adrenergic

stimulation can block this transmission. Symptoms begin with

stomach discomfort and progress to salivation changes, sweating, dizziness, lethargy, retching, and emesis. The risk of motion

sickness is low in children younger than 2 years of age. The risk

is highest in children and adolescents compared with adults, and

higher in women than men. In some individuals, sensitivity to

motion sickness diminishes with time.2 Travel by boat is most

likely to cause symptoms; air, car, and train travel is less likely.3,4

The severity of the motion sickness is highly dependent on the

individual and also varies with the weather and position in the

plane or boat. Because of P.C.’s history and her travel plans, she

is at high risk for recurrence of her motion sickness symptoms.

Nonpharmacologic measures or natural remedies may be useful for reducing motion sickness.2 These include riding in the

middle of the boat or plane where the motion is less dramatic,

lying in a semirecumbent position, fixing the vision on the horizon, avoiding reading, and closing the eyes if below deck or in

the cabin. Many people recommend keeping active on a ship

to “get their sea-legs” faster through habituation. The effectiveness of acupressure at the P6 point of the wrist (about three

fingerbreadths above the wrist) is unclear. A controlled-stimulus

trial compared two brands of wristbands with placebo; neither

band was more effective than placebo in preventing symptoms of

motion sickness.5 Studies of ginger preparations also are equivocal. The action of ginger may be through enhanced gastric

emptying and not on the vestibular system.6,7

Overview of Treatment

CASE 6-1, QUESTION 2: For P.C., what medications are

available to prevent and treat motion sickness symptoms?

Anticholinergic agents and antihistamines that cross the

blood–brain barrier effectively prevent and treat motion

sickness.3,4 In general, these medications are more effective in

preventing than treating established symptoms. 5-HT3 receptor

antagonists and NK1 receptor antagonists have not been shown

to be effective in preventing motion sickness.2,6 Nonsedating antihistamines are not as effective as other antihistamines because

they do not sufficiently cross the blood–brain barrier.2,3 Scopolamine has been well studied for the prevention of motion sickness and is highly effective.2,8 In a controlled trial, scopolamine

was more effective than promethazine and both were more

101Nausea and Vomiting Chapter 6

TABLE 6-1

Medications for Prevention or Treatment of Motion Sickness in Adults

Medication (Trade Name) Dosage Recommended Use Adverse Effects

Scopolamine

(Transderm-Scop)

1.5 mg TOP behind the ear every 3 days.

Apply at least 3 hours (preferably

6–8 hours) before exposure.

Long-term exposure (>6 hours) to

moderate to intense stimulus.

Alternative treatment for shorter or

milder stimulus.

Dry mouth, drowsiness,

blurred vision, confusion,

fatigue, ataxia

Dimenhydrinate

(Dramamine)

50–100 mg PO every 4–6 hours (max

400 mg/day). May be taken PRN or on

scheduled basis if required.

Short- or long-term exposure to mild to

moderate stimulus. Alternative for

intense stimulus.

Drowsiness, dry mouth,

thickening of secretions,

dizziness

Promethazine (Phenergan) 25 mg PO every 4–6 hours. May be taken

PRN or on scheduled basis if required.

25–50 mg IM every 4–6 hours for

established severe symptoms. May be

taken PRN or on scheduled basis if

required.

In combination with dextroamphetamine

for short exposure to intense stimulus.

Alternative for longer or milder

stimulus.

Drowsiness, orthostatic

hypotension, dry mouth

Meclizine (Antivert, Bonine) 12.5–50 mg PO every 6–24 hours. May be

taken PRN or on scheduled basis if

required.

Alternative for mild stimulus or in

combination for moderate to severe

stimulus.

Drowsiness, dry mouth,

thickening of secretions,

dizziness

Dextroamphetamine

(Dexedrine)

5–10 mg PO every 4–6 hours. May be

taken PRN or on scheduled basis if

required.

In combination with promethazine for

short exposure of intense stimulus.

Restlessness, abuse potential,

insomnia, overstimulation,

tachycardia, palpitations,

hypertension

Cyclizine (Marezine) 50 mg PO every 4–6 hours (max 200

mg/day). May be taken PRN or on

scheduled basis if required.

Alternative for mild stimulus situations. Drowsiness, dry mouth,

IM, intramuscular; PO, oral; PRN, as needed; TOP, topically.

Source: Priesol AJ. Motion sickness. Up To Date. http://www.uptodate.com/contents/motion-sickness?source=search result&selectedTitle=1%7E51. Accessed

September 27, 2010; Shupak A, Gordon CR. Motion sickness: advances in pathogenesis, prediction, prevention, and treatment. Aviat Space Environ Med. 2006;77:1213.

effective than placebo, meclizine, or lorazepam.9 Scopolamine

is available as a topical patch, which bypasses the problem of GI

symptoms associated with motion sickness. Table 6-1 describes

medications effective for motion sickness based on the intensity

of the stimulus, adult doses, and potential adverse effects.

Because P.C. is a susceptible individual in a moderate-severe

stimulus situation, prevention with a scopolamine patch applied

behind the ear every 3 days, starting 6 to 8 hours before departure, should be recommended. If she experiences breakthrough

symptoms, dimenhydrinate or promethazine may be useful. She

should be advised about the potential adverse effects of these

agents, which include drowsiness, confusion, and dry mouth.

CHEMOTHERAPY-INDUCED NAUSEA

AND VOMITING

Clinical Presentation and Risk Factors

CASE 6-2

QUESTION 1: M.C., a 54-year-old woman with breast cancer, is in the clinic today to receive her first cycle of

chemotherapy. Her chemotherapy will consist of intravenous (IV) docetaxel 75 mg/m2, carboplatin dosed to

achieve an area under the curve (AUC) of 6 mg/mL/minute.

This will be repeated every 21 days. In addition, she will

receive trastuzumab 4 mg/kg IV for one dose, then 2 mg/

kg/week for 17 weeks. M.C. does not drink alcohol or

smoke. Her only other medical condition is adult-onset diabetes, which is controlled with metformin and diet. She has

had four children, now all grown, and had substantial morning sickness with each of her pregnancies. M.C.’s neighbor

has told her that all chemotherapy causes severe nausea

and vomiting. How likely is M.C. to experience nausea and

vomiting?

Chemotherapy-induced nausea and vomiting (CINV) occurs

in many patients receiving chemotherapy for cancer.1 The mechanisms of the emetic response described at the beginning of

this chapter apply to CINV as well. The major neurotransmitter

receptors involved in these pathways include 5-HT3, NK1, and

dopamine receptors. CINV can occur in different phases. Acutephase CINV symptoms occur within a few hours after the administration of the chemotherapy. These symptoms often peak several hours after administration and can last for the first 24 hours.

Some antineoplastic agents can also cause nausea and vomiting

symptoms for a longer time after chemotherapy administration.

These delayed CINV symptoms peak in about 2 to 3 days and can

last 6 to 7 days. Some patients experience acute symptoms without delayed symptoms. Some other patients experience delayed

symptoms without acute symptoms, and many patients experience CINV in both the acute and delayed phases. Some patients

who have received previous chemotherapy treatments may experience a conditioned response in which they have symptoms even

before the chemotherapy starts. This is called anticipatory nausea

and vomiting, and it is difficult to treat because it is primarily triggered by poor nausea and vomiting control in previous cycles.

Breakthrough nausea and vomiting occur if the primary prophylactic antiemetics fail to work completely. Of course, regardless of

the time course and cause, these are very distressing, unpleasant,

and disruptive symptoms for the patient.

The likelihood of CINV depends on several factors.1 Patientrelated factors that increase the risk of acute-phase CINV include

age younger than 50 years, female sex, poor control of symptoms in prior cycles, history of motion sickness or nausea

with pregnancy, anxiety, or depression. A significant history of

alcoholism actually protects against CINV. Delayed symptoms

are more common in women, in those who have had poor

102 Section 1 General Care

emetic control in the acute phase, and in patients with anxiety or

depression.

Chemotherapy-related factors also predict the likelihood of

symptoms. Factors such as shorter infusion time, higher dose,

and more chemotherapy cycles increase the risk of CINV. With

multiday chemotherapy regimens, the symptoms usually peak

on about the third to fourth day of chemotherapy, when the

acute symptoms caused by the later days’ doses are overlapping

with the delayed symptoms from the first days’ doses. The most

predictive factor, however, is the chemotherapy agent’s inherent

ability to cause CINV, or its emetogenicity.1,10,11 Antineoplastics

that are most likely (>90% of patients) to cause symptoms are

classified as highly emetogenic chemotherapy. Agents that cause

nausea and vomiting in 30% to 90% of patients are classified as

moderate-risk agents. Low emetogenicity agents cause symptoms in 10% to 30% of patients. Other chemotherapy agents

have a minimal risk, causing CINV in less than 10% of patients.

Table 6-2 lists selected chemotherapy agents in the various emetogenicity classes, noting that references differ in the estimation

of emetic risk for some antineoplastic agents. The emetogenicity

risk also depends on the dosage used and the route of administration.

Certain antineoplastic agents are more likely to cause

delayed CINV symptoms. These include cisplatin, carboplatin,

cyclophosphamide, doxorubicin, epirubicin, ifosfamide, and to

a lesser degree, irinotecan and methotrexate. Patients receiving

more than one of these agents are at high risk for delayed symptoms.

Most chemotherapy agents are given in combinations,

rather than as single agents. Estimating the emetogenicity of

chemotherapy combinations has always been difficult. The

chemotherapy regimen that contains cyclophosphamide and

either doxorubicin or epirubicin for breast cancer in females is

highly emetogenic (symptoms in>90% of patients). The primary

literature of the regimen should always be consulted to determine the emetic risk. Should that not be available, the antiemetic

regimen should be geared toward the chemotherapy agent with

the highest emetogenicity level given on that day.1,12,13 For example, in a chemotherapy combination with one high-risk agent

and one with a moderate risk, the antiemetic regimen should be

appropriate for the high-risk chemotherapy agent.

Antiemetic efficacy, or complete emetic response, is usually

defined as no emesis and no nausea or only mild nausea in the

first 24 hours after chemotherapy administration. With currently

recommended antiemetic regimens, most, but not all, patients

will be protected from emesis in the acute phase (first 24 hours).

Nausea, however, is more difficult to control. In addition, delayed

CINV symptoms are more difficult to prevent.

Overview of Treatment

CASE 6-2, QUESTION 2: M.C. is at moderate risk for acute

CINV. Her personal risk factors include female sex, history of

morning sickness with pregnancy, and being a nondrinker.

The docetaxel has a low risk of acute CINV, the carboplatin

has a moderate risk of acute CINV with a high risk of delayed

CINV, and the trastuzumab has a minimal risk of acute CINV.

What antiemetics are available for M.C.?

Appropriate antiemetic therapy is based on the emetogenicity

of the chemotherapy regimen and patient risk factors. Because

the pathophysiologic response of nausea and vomiting involves

many neurotransmitters, combinations of antiemetics from different therapeutic classes will be more effective in most situations

than a single agent. The predominant classes of antiemetics used

for CINV include 5-HT3 antagonists, the NK1 antagonist, and

corticosteroids.

5-HT3 ANTAGONISTS

The 5-HT3 antagonists inhibit the action of serotonin in the GI

tract and the CNS and thereby block the transmission of emetic

signals to the VC. 5-HT3 antagonists are both highly effective and

have minimal side effects. Several agents and dosage forms in this

class are now available: ondansetron, granisetron, dolasetron, and

palonosetron. Dosages of these agents are shown in Table 6-3.

The route of administration should be matched to the clinical status of the patient. Oral tablets are appropriate for most

patients, but intravenous, topical, or oral dissolving tablet formulations may be needed in patients who cannot take oral medications.

These agents have been widely studied, and some commonalities have emerged. All of the 5-HT3 antagonists are considered

to have equivalent efficacy.14–19 All of these agents have a threshold effect and so a sufficiently large dose must be given to block

the relevant receptors. In addition, the dose-response curve is

relatively flat, such that escalating the dose beyond the threshold dose does not enhance efficacy. When given in appropriate

doses, all of these agents have similar efficacy for acute CINV, with

response rates of 60% to 80%, depending on study design.1,12,14–19

The effectiveness of the 5-HT3 receptor antagonists is enhanced

by the addition of dexamethasone. The response rate increases

by about 15% to 20% in regimens that include dexamethasone

and a 5-HT3 antagonist.17,20 Oral and IV 5-HT3 administration

are equally effective assuming the patient can take oral medications. The side effects of all the 5-HT3 antagonists are similar and fairly mild and include headache, constipation, diarrhea,

and transient elevations of liver function tests. 5-HT3 antagonists

are one component of optimal antiemetic prophylaxis for acute

CINV. They are not more effective than agents from other classes

(notably dexamethasone, aprepitant, or prochlorperazine) for

delayed CINV.17,21–23 5-HT3 antagonists, therefore, are not generally recommended for delayed CINV. The 5-HT3 antagonists

are metabolized by different cytochrome P-450 enzymes, including CYP1A2, CYP2D6 and CYP3A4. Differences in the metabolic

rate of 5-HT3 antagonists attributable to CYP2D6 polymorphisms might account for differences in efficacy among individual

patients.17 However, these differences are not used clinically to

choose initial antiemetic therapy at this time.

Ondansetron, granisetron, and dolasetron have similar pharmacokinetic parameters. Palonosetron, the newest member of

the 5-HT3 antagonist family, is distinguished by a longer elimination half-life than others in its class. Palonosetron was compared

with single doses of 5-HT3 antagonists with shorter half-lives

in various studies. Palonosetron showed equivalent or somewhat superior efficacy, but questions have arisen regarding the

lack of comparable treatment in the control arms.18,24 One

group of researchers described a three-drug combination of

palonosetron, dexamethasone, and aprepitant in a noncomparative, phase II study with moderately emetogenic chemotherapy, and found that the three-drug combination was safe and

effective.25 Whether palonosetron is equivalent or superior

to other 5-HT3 antagonists should be determined by trials

that compare palonosetron with another 5-HT3 antagonist,

with both treatment arms also containing dexamethasone and

aprepitant in the acute and delayed phases. These trials have

yet to be conducted. Currently, palonosetron is substantially

more expensive than the generic forms of the other 5-HT3

antagonists.

Palonosetron is normally administered as a single 0.25-mg IV

or 0.5-mg oral (PO) dose before chemotherapy. With its long

elimination half-life (about 40 hours), palonosetron should be

103Nausea and Vomiting Chapter 6

TABLE 6-2