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            Information for Physicians


Nausea and vomiting
208/04466


Nausea and vomiting: introduction

Nausea and vomiting may be among the discomforting, distressing side effects of
cancer therapies.  Despite advances in the pharmacologic and nonpharmacologic
management, nausea and vomiting remain two of the most dreaded side effects by
cancer patients and their families.[1,2]

Prevention and control of nausea and vomiting is paramount in the treatment of
cancer patients, as these can result in serious metabolic derangements,
nutritional depletion, deterioration of a patient's physical and mental status,
withdrawal from potentially useful and curative antineoplastic treatment, and
degeneration of self-care and functional ability.[3-5]

Nausea is a subjective phenomenon of an unpleasant, wavelike sensation
experienced in the back of the throat and/or the epigastrium that may or may
not culminate in vomiting.  It is often described as "feeling sick to the
stomach."[6,7] Vomiting is the forceful expulsion of the contents of the
stomach, duodenum, or jejunum through the oral cavity.  Retching is the attempt
to vomit without bringing anything up and is also described as "dry heaves."

Although nausea and vomiting are often used synonymously, some studies suggest
that they are distinct entities with different component.
s.[4,6,8]  Patients
have made the distinction between nausea and vomiting and indicate that nausea
is far more distressing than vomiting.[6,9,10]

Nausea and vomiting are also commonly classified as anticipatory, acute, or
delayed, especially when referring to chemotherapy-induced symptoms.
Anticipatory nausea and vomiting (ANV) largely occurs prior to or during
chemotherapy administration and, to a lesser extent, radiation therapy.  Acute
nausea and vomiting occurs within a few minutes to several hours after drug
administration and usually resolves within 24 hours.  Delayed nausea and
vomiting occurs several hours after chemotherapeutic drugs are given and can
last several days.  Certain drugs, such as cisplatin, cyclophosphamide,
doxorubicin, and ifosfamide, are associated with delayed nausea and
vomiting.[11]

References:
  1. Coates A, Abraham S, Kaye SB, et al.: On the receiving end - patient
     perception of the side-effects of cancer chemotherapy.  European Journal
     of Cancer and Clinical Oncology 19(2): 203-208, 1983.
  2. Craig JB, Powell BL: The management of nausea and vomiting in clinical
     oncology.  American Journal of the Medical Sciences 293(1): 34-44, 1987.
  3. Richardson JL, Marks G, Levine A: The influence of symptoms of disease
     and side effects of treatment on compliance with cancer therapy.
     Journal of Clinical Oncology 6(11): 1746-1752, 1988.
  4. Laszlo J, Ed.:  Antiemetics and Cancer Chemotherapy. Baltimore: Williams
     & Wilkens, 1983.
  5. Ingle RJ, Burish TG, Wallston KA: Conditionability of cancer chemotherapy
     patients.  Oncology Nursing Forum 11(4): 97-102, 1984.
  6. Rhodes VA, Watson PM, Johnson MH, et al.: Patterns of nausea, vomiting,
     and distress in patients receiving antineoplastic drug protocols.
     Oncology Nursing Forum 14(4): 35-44, 1987.
  7. Rhodes VA, Watson PM, Johnson MH: Development of reliable and valid
     measures of nausea and vomiting.  Cancer Nursing 7(1): 33-41, 1984.
  8. Salla.
n SE, Cronin CM:  Nausea and vomiting.  In: DeVita VT, Hellman S,
     Rosenberg SA, Eds.: Cancer: Principles and Practice of Oncology.
     Philadelphia: JB Lippincott Company, 2nd Edition, 1985, pp 2008-2013.
  9. Rhodes VA, Watson PM, Johnson MH: Patterns of nausea and vomiting in
     chemotherapy patients: a preliminary study.  Oncology Nursing Forum
     12(3): 42-48, 1985.
 10. Rhodes VA, Watson PM, Johnson MH: Association of chemotherapy related
     nausea and vomiting with pretreatment and posttreatment anxiety.
     Oncology Nursing Forum 13(1): 41-47, 1986.
 11. Moreno I, Rosell R, Abad A, et al.: Comparison of three protracted
     antiemetic regimens for the control of delayed emesis in
     cisplatin-treated patients.  European Journal of Cancer 28A(8/9):
     1344-1347, 1992.

Nausea and vomiting: neurophysiology

Neurophysiology of Nausea and Vomiting

Progress has been made in understanding the neurophysiologic mechanisms that
control nausea and vomiting.  Both are controlled or mediated by the central
nervous system but by different mechanisms.  Nausea is mediated through the
autonomic nervous system.  Vomiting results from the stimulation of a complex
reflex that is coordinated by the true vomiting center, located in the
dorsolateral reticular formation near the respiratory center of the medulla.
The true vomiting center, which ultimately controls all emesis, may be
stimulated from several neurologic pathways.  Afferent input comes from the
chemoreceptor trigger zone (CTZ), located in the floor of the fourth ventricle.
The CTZ responds to the following:  the presence of noxious stimuli in the
blood and spinal fluid; vagal visceral and other sympathetic afferents from the
viscera (i.e., sympathetic visceral response to inflammation, ischemia, and
irritation of the GI tract); vestibulocerebellar afferents from the labyrinth
of the inner ear in response to body motion; and afferent input from the
cerebral cortex and the limbic system in response .
to stimulation of the senses
(particularly smell and taste), distress, pain, and increases in intracranial
pressure.  It is believed that input into the CTZ is the major cause of
chemotherapy-induced nausea and vomiting.  The central pathways appear to
converge on the true vomiting center and contain distinct types of
neurotransmitter receptors that respond to the specific chemicals dopamine,
histamine, acetylcholine, serotonin, norepinephrine, and glutamine.[1-5]  The
effect of these multiple pathways upon the true vomiting center is complex.  In
ANV, however, the CTZ is probably not directly stimulated.

References:
  1. Craig JB, Powell BL: The management of nausea and vomiting in clinical
     oncology.  American Journal of the Medical Sciences 293(1): 34-44, 1987.
  2. Sallan SE, Cronin CM:  Nausea and vomiting.  In: DeVita VT, Hellman S,
     Rosenberg SA, Eds.: Cancer: Principles and Practice of Oncology.
     Philadelphia: JB Lippincott Company, 2nd Edition, 1985, pp 2008-2013.
  3. Borison HL, Wang S: Physiology and pharmacology of vomiting.
     Pharmacological Reviews 5: 195-230, 1953..
  4. Guyton AC:  Textbook of Medical Physiology. Philadelphia: W.B. Saunders,
     6th ed., 1981..
  5. Borison HL, McCarthy LE:  Neuropharmacologic mechanisms of emesis.  In:
     Laszlo J, Ed.: Antiemetics and Cancer Chemotherapy. Baltimore: Williams
     & Wilkens, 1983, pp 6-20.

Nausea and vomiting: incidence and etiology

Not all cancer patients will experience nausea and/or vomiting.  The most
common causes are emetogenic chemotherapy drugs and radiation therapy to the
gastrointestinal tract, liver, or brain.  Other possible causes include fluid
and electrolyte imbalances such as hypercalcemia, volume depletion, or water
intoxication; tumor invasion or growth in the gastrointestinal tract, liver, or
central nervous system, especially the posterior fossa; constipation; certain
drugs such as narcotics; infection or septicemia; uremia; and psychogenic
factors.  Clinic.
ians treating nausea and vomiting must be alert to all
potential causes and factors, especially in cancer patients who may be
receiving combinations of several treatments and medications.

Anticipatory nausea and vomiting refers to a conditioned response in which
nausea and vomiting occur prior to treatments and/or specific environmental
stimuli (i.e., objects, odors, tastes, and smells).  Approximately 10-44% of
patients receiving chemotherapy experience nausea and/or vomiting prior to or
during chemotherapy infusions.[1-3]  While the onset of ANV varies among
patients, the pattern is frequently apparent by the fourth or fifth course of
treatment.  No single factor is characteristic of the development of ANV
symptoms.  Recent evidence indicates that certain variables can predict which
patients will develop ANV.  These variables include patients who receive a drug
regimen high in emetogenic potential, experience symptom and psychosocial
distress, experience mood disturbances, and who demonstrate a limited ability
to cope with the stress of the treatment.[4]  Variables correlated with the
development of ANV include:[1,5-7]

  - Emetogenicity of chemotherapy received.

  - Sweating after last chemotherapy.

  - Feeling warm or hot after last chemotherapy.

  - Severity of post-treatment nausea and vomiting.

  - Number of chemotherapy cycles received.

  - High state- and trait-anxiety levels (state anxiety is a measure of an
    individual's feelings of anxiety at a specific moment, while trait anxiety
    reflects how individuals generally feel about themselves and their
    responses to stress).

  - Abnormal taste sensations during chemotherapy administration.

  - Susceptibility to motion sickness.

  - Delayed onset of postchemotherapy nausea and vomiting.

  - Age (negatively correlated) less than 50.

  - Post-treatment dizziness and lightheadedness.

Although anxiety may not be the sole factor, it may facilitate the development
of ANV in the presence of oth.
er identified factors.  State- and trait-anxiety
levels have been observed to be significantly higher in patients with
anticipatory nausea, and increased anxiety has been found to decrease the
patient's ability to develop coping strategies in the event of nausea and
vomiting.[6]

The direct effect of age on the development of ANV has not been clearly
demonstrated.  Although it has been suggested that younger adults are more
susceptible to ANV, whether younger patients may be receiving more aggressive
chemotherapy treatments than their older counterparts, and subsequently
experiencing more severe post-treatment nausea and vomiting, remains
unclear.[1]

Several myths concerning nausea and vomiting must be dispelled.  The first is
that nausea and vomiting are inevitable from cancer treatments.  Many cancer
patients may never experience these symptoms.  A second myth centers on the
belief that a cancer patient should experience nausea and vomiting for the
treatment to be effective.  There appears to be no correlation between these.
Finally, it is common to believe that nothing can be done about nausea and
vomiting.  In the vast majority of cancer patients who will experience these
symptoms, nausea and vomiting can be prevented or controlled.

By far, chemotherapy is the most common cause of nausea and vomiting.  The
incidence and severity in persons receiving chemotherapy varies according to
many factors, including the particular drug, dose, schedule of administration,
route, and individual patient variables.

Although every chemotherapy drug in use has the potential for causing nausea
and vomiting, drugs are classified based on their emetogenic potential:[8]

Severe emetogenic potential drugs (greater than 90% of persons will experience
nausea and vomiting) include the following:

  cisplatin
  dacarbazine
  streptozocin
  mechlorethamine
  cytarabine (high dose)

High emetogenic potential drugs (60-90% of persons will experience nausea and
vomiting) include the follo.
wing:

  cyclophosphamide
  carmustine
  semustine
  lomustine
  procarbazine
  methotrexate (high dose)
  dactinomycin
  ifosfamide
  carboplatin

Moderate emetogenic potential drugs (30-60% of persons will experience nausea
and vomiting) include the following:

  L-asparaginase
  daunorubicin
  doxorubicin
  mitomycin-C
  5-azacytidine
  5-fluorouracil
  hexamethylmelamine
  etoposide

Low emetogenic potential drugs (10-30% of persons will experience nausea and
vomiting) include the following:

  bleomycin
  cytarabine
  methotrexate
  hydroxyurea
  6-mercaptopurine
  vinblastine
  thiotepa


Finally, very low emetogenic potential drugs (less than 10% of persons will
experience nausea and vomiting) include the following:

  busulfan
  androgens
  estrogens
  corticosteroids
  thioguanine
  vincristine
  progestins

Besides emetogenic potential, however, the dose and schedule used are also
extremely important factors.  For example, a drug with a low emetogenic
potential given in high doses would have a dramatic increase in the potential
to induce nausea and vomiting.  Standard doses of cytarabine rarely produce
nausea and vomiting, but these are often seen with high doses of this drug.
Another factor to consider is the use of drug combinations.  Because most
patients receive combination chemotherapy, the emetogenic potential of all of
the drugs combined and individual drug doses needs to be considered.

Although patients receiving radiation therapy can experience ANV, in general,
patients receiving radiation to the GI tract or brain have the greatest
potential for nausea/vomiting as a side effect.  Because cells of the GI tract
are dividing quickly, they are quite sensitive to radiation therapy.  Radiation
to the brain is believed to stimulate the brain's vomiting center or CTZ.
Similar to chemotherapy, radiation dose factors also play a role in determining
the possible occurrence of nausea and vomiting.  In general, the higher the
daily fractional dose and total.
 dose of radiation, and the greater the amount
of tissue that is irradiated, the higher the potential for nausea and vomiting.
In addition, the more of the GI tract irradiated, the higher the potential for
nausea and vomiting.  Total body irradiation before bone marrow transplant, for
example, has a high probability for nausea and vomiting as acute side effects.

Nausea and vomiting from radiation may be acute and self-limiting.  It usually
occurs one-half to several hours after treatment.  Patients report that it
improves on days that they are not being treated.  There are also cumulative
effects that may occur in patients receiving radiation therapy to the GI tract.
Nausea and vomiting have also been reported in patients receiving
radiosensitizers, such as SR 2508.

References:
  1. Morrow GR, Lindke J, Black PM: Predicting development of anticipatory
     nausea in cancer patients: prospective examination of eight clinical
     characteristics.  Journal of Pain and Symptom Management 6(4): 215-223,
     1991.
  2. Nesse RM, Carli T, Curtis GC, et al.: Pretreatment nausea in cancer
     chemotherapy: a conditioned response?  Psychosomatic Medicine 42(1):
     33-36, 1980.
  3. Wilcox PM, Fetting JH, Nettesheim KM, et al.: Anticipatory vomiting in
     women receiving cyclophosphamide, methotrexate, and 5-FU (CMF) adjuvant
     chemotherapy for breast carcinoma.  Cancer Treatment Reports 66(8):
     1601-1604, 1982.
  4. Pickett M: Determinants of anticipatory nausea and anticipatory vomiting
     in adults receiving cancer chemotherapy.  Cancer Nursing 14(6): 334-343,
     1991.
  5. Nerenz DR, Leventhal H, Easterling DV, et al.: Anxiety and drug taste as
     predictors of anticipatory nausea in cancer chemotherapy.  Journal of
     Clinical Oncology 4(2): 224-233, 1986.
  6. Andrykowski MA, Redd WH: Longitudinal analysis of the development of
     anticipatory nausea.  Journal of Consulting and Clinical Psychology
     55(1): 36-41, 1987.
  7. Chin SB, Kucuk O.
, Peterson R, et al.: Variables contributing to
     anticipatory nausea and vomiting in cancer chemotherapy.  American
     Journal of Clinical Oncology 15(3): 262-267, 1992.
  8. Chase JL, Staggs RJ: Outpatient treatment of chemotherapy induced nausea
     and vomiting.  Outpatient Chemotherapy 3(3): 4, 1990.

Post-treatment nausea and vomiting: management

Antiemetic agents are the most common intervention in the management of
treatment-related nausea and vomiting.  The basis for antiemetic therapy is the
neurochemical control of vomiting.  Although the exact mechanism is not well
understood, the CTZ is known to contain receptors for histamine (H1 and H2),
dopamine, acetylcholine, and opiates.  Antiemetics act by blocking the
receptors for these substances, thereby inhibiting their stimulation of the
CTZ.  Several studies have been done to show the effectiveness of antiemetics
in preventing and controlling treatment-related nausea and vomiting.  With the
advent of cisplatin, a chemotherapy drug producing severe nausea, a more
aggressive approach to the study and use of antiemetics has emerged.

Most drugs used to treat nausea and vomiting can be classified into the
following groups:  dopamine antagonists, serotonin antagonists, and other
antagonists.  Examples of dopamine antagonists include phenothiazines,
substituted benzamides, and butyrophenones.  Prochlorperazine is perhaps the
most frequently used antiemetic, and with low doses is generally effective in
preventing nausea associated with radiation therapy and in treating nausea and
vomiting attributed to very low to moderately emetogenic chemotherapy drugs.
It is a phenothiazine and can be given by mouth, IM, IV, and rectally.  It is
usually given in the 10-50 mg dose range (Pediatric dose:  6 mg every 4 to 6
hours).  Higher doses of prochlorperazine are also used intravenously for high
emetogenic potential chemotherapy drug treatments.  The most common side
effects of this drug are extrapyramidal reactions.
 and sedation.  Other
phenothiazines include chlorpromazine (also available IM, IV, PO, and rectally,
10-50 mg dose range (Pediatric dose:  >12 years old - 10 mg every 6 to 8 hours;
<12 years old - 5 mg every 6 to 8 hours) and thiethylperazine (given IM, IV,
PO, and rectally, 5-10 mg dose range).  The phenothiazines act on the true
vomiting center.

Metoclopramide, a substituted benzamide, is often used in chemotherapy regimens
using cisplatin.  It is an effective antiemetic but has a relatively short
half-life, requiring frequent administrations.  It acts on the CTZ periphery
and can be administered PO and IV in normal dose ranges of 1-2 mg/kg.  It is
associated with the side effects of dystonia and akathisia, especially in
persons under the age of 30, often requiring concomitant diphenhydramine for
prevention of dystonic reactions.  Benztropine mesylate, as well as
diphenhydramine, can be used for treatment of dystonic reactions.[1]

A third dopamine antagonist used less frequently than prochlorperazine and
metoclopramide is droperidol.  This drug is similar in chemical structure to
the phenothiazines.  It is in a class of drugs classified as butyrophenones and
is administered IM or IV in the 1-2.5 mg dose range and can produce tachycardia
or orthostatic hypotension.  Haloperidol, another butyrophenone, is
administered IM, IV, or PO in the dose range of 1-4 mg and can have the same
primary side effects as droperidol.  The site of action for the butyrophenones
is also on the CTZ.

A serotonin antagonist, ondansetron, was approved by the FDA in 1991 for use as
an antiemetic.  Several studies have demonstrated its enhanced efficacy and low
toxicity compared to other agents used in the management of nausea and vomiting
induced by chemotherapy.[2-5]  Ondansetron (0.15 mg/kg IV) is given 15 minutes
prior to chemotherapy; the same dose is repeated at 4 hours and 8 hours.
Combination with dexamethasone has shown increased efficacy.[6,7]  Other dosing
schedules, such as l.
arge single doses (32 mg) 1/2 hour prior to chemotherapy or
as a continuous infusion (1 mg/hr for 24 hours) or oral administration, have
been used.[7-11]  Side effects include headache, constipation, fatigue, dry
mouth, diarrhea, and transient asymptomatic elevations in liver function tests,
i.e. alanine transaminase/aspartate transaminase.  The frequency of
extrapyramidal side effects and sedation appears to be less with serotonin
antagonists than with other classes of antiemetics, however, the drug is
expensive.  Other serotonin antagonists are also under evaluation.[12-14]

Several other antagonists are also commonly used in the prevention and
treatment of nausea and vomiting.  These include steroids (dexamethasone,
methylprednisolone), benzodiazepines (lorazepam, diazepam), and the
cannabinoids (dronabinol, nabilone).

Steroids can treat nausea and vomiting as single agents, but are more often
used in antiemetic drug combinations.[15]  Their mechanism of action related to
emesis is not fully understood, but they may affect prostaglandin activity in
the brain.[16]  Dexamethasone is often the treatment of choice in treating
nausea and vomiting in a person receiving radiation to the brain, as it also
reduces brain edema.  It is administered PO, IM, or IV in the dose range of
8-40 mg (Pediatric dose:  0.25-0.5 mg/kg).  For chemotherapy-related nausea and
vomiting, it is often given intravenously before and after the chemotherapy is
given, then orally for delayed nausea and vomiting.  Long-term administration
of dexamethasone can produce several side effects, including muscle weakness
(especially in the thighs and upper arms), lethargy, weight gain, GI
irritation, and mood changes.

If given intravenously, dexamethasone should be given slowly since rapid
infusion can cause acute transient rectal pain.[17]

Benzodiazepines, such as lorazepam, are becoming more popular in the prevention
and treatment of treatment-related nausea and vomiting, especially with severe
emet.
ogenic chemotherapy given to children.[18]  These drugs act on the higher
CNS structures, the brainstem, and spinal cord, and essentially produce both a
sedative and amnesic effect.  Lorazepam can be administered PO, IM, IV, and
also sublingually.  Dose range is 0.5-3 mg in adults and 0.03-0.05 mg/kg in
children.

Cannabinoids, the last category of non-dopamine antagonists, also target the
higher CNS structures to prevent nausea and vomiting.  Synthetic drugs similar
to marijuana include dronabinol and nabilone.  Because of cultural, societal,
and financial constraints, these drugs are often not the first selected agents
for antiemetics but may be best accepted and most useful in young adults.
These drugs are administered orally and may produce a euphoria or "high,"
drowsiness, or hypotension.  In one double-blind randomized study of patients
receiving cisplatin, adrenocorticotropic hormone (ACTH) was superior to placebo
when given in combination with metoclopramide and dexamethasone.  A dose of 1
mg ACTH decreased the incidence and severity of delayed emesis for the 24-72
hours after therapy.[19]

Wickham, Krasnow and Sagar have published comprehensive overviews of antiemetic
drugs, their actions, doses, and possible side effects.[17,20-22]  Gralla et
al. [23] have outlined methodology for use in designing antiemetic trials.

Besides single antiemetic agents, combination antiemetic regimens are also used
and have become increasingly popular with highly emetogenic chemotherapy
treatment programs.  A combination of several drugs can be used to attack
nausea and vomiting from several sites and mechanisms of action.  Most
combination drug regimens combine a dopamine antagonist with those having no
dopamine-blocking effect.  An example of a combination drug regimen is the
in-patient administration of metoclopramide, dexamethasone, and lorazepam for a
cisplatin-containing drug regimen in the following doses and schedule:

  metoclopramide 2 mg/kg IV before chemotherapy