Guide to Pain Management in Low-Resource Settings

Guide to Pain Management in Low-Resource Settings
Justin Baker, Raul Ribeiro, and Javier Kane
Chapter 22
Hematologic Cancer with Nausea and Vomiting
Case report
Michael is a 23-year-old man with recurrent lympho-
blastic lymphoma in his bone marrow and central ner-
vous system (CNS) who is receiving end-of-life care with 
palliative  chemotherapy. Five days ago, Michael started 
on a course of oral cyclophosphamide (see Table 1 for 
emetogenic properties of chemotherapy) with the inten-
tion of prolonging a life of good quality. Michael’s chief 
complaint at this time is severe nausea accompanied by 
vomiting 2 or 3 times per day. Th
  e main concern of Mi-
chael’s parents is his inability to eat or drink anything 
considerable. Michael is currently receiving morphine 30 
mg orally every 4 hours, mostly to control his headaches. 
He is on no other medications. Further history reveals 
that Michael’s nausea and vomiting have been increasing 
in severity over the past 3 days (he started the cyclophos-
phamide 5 days ago). He has not had a bowel movement 
for 7 days.
Why is treatment of nausea          
and vomiting so important?
Nausea is defi ned as a feeling of sickness in the stomach 
and is characterized by an urge to vomit. Vomiting is the 
forceful expulsion of the contents of the stomach and 
proximal small intestine. Nausea and vomiting (N/V) are 
common symptoms in dying patients and arise as
 
a re-
sult of either treatment-related toxicity (disease-specifi c 
treatment or palliative treatment) or complications di-
rectly or indirectly related to the disease. More than half 
of cancer patients who are dying experience signifi cant 
nausea, and nearly one-third experience vomiting. Th
 e 
clinical picture of N/V is often multifactorial. Regardless 
of the etiology, the symptoms of N/V can interfere with 
patients’ nutritional status and their enjoyment of eat-
ing and drinking and can signifi cantly aff ect their quality 
of life and the quality of their death. When not properly 
managed, N/V interferes with a patient’s nutritional sta-
tus, hydroelectrolytic homeostasis, mental status, clinical 
performance, and compliance with treatment. Clinicians 
therefore have an ethical imperative to prevent, screen, 
assess, treat, and follow up N/V to ensure the best pos-
sible care for dying cancer patients.
What are the main pathways 
involved in the pathophysiology    
of nausea and vomiting?
Th
 e pathophysiology of nausea and vomiting is fairly 
well characterized. Th
  e vomiting center receives aff erent 
input from four neuronal pathways that carry emeto-
genic signals:
Peripheral pathways from the gastrointestinal 
(GI) tract through the vagus and splanchnic nerves. Th
 e 
GI tract may elicit nausea through sensations of irrita-
tion by medications, tumor infi ltration, obstruction, dis-
tension, or constipation or fecal impaction.

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Justin Baker et al.
Neuronal pathways from the chemoreceptor 
trigger zone (CTZ). Th
  e CTZ is located in the fl oor of 
the fourth ventricle and lacks a true blood-brain bar-
rier. Th
  is allows the zone to sense fl uctuations in the 
concentration of certain substances in the blood-
stream. Th
  e CTZ may also be stimulated by posterior 
fossa tumors.
Vestibular pathways from the labyrinth
. Vestibu-
lar pathways may be stimulated by vestibular disease such 
as vertigo, middle-ear infections, or motion sickness.
Cortical pathways in response to sensory or psy-
chogenic stimuli.
 Cortical stimulation may come from a 
CNS or meningeal tumor, increased intracranial pres-
sure, anxiety, or uncontrolled pain.
How are nausea and               
vomiting classifi ed?
Nausea and vomiting are usually classified as acute, 
delayed, refractory, anticipatory, or breakthrough. 
Acute emesis, which appears to be mediated by se-
rotonin, occurs within 3 to 4 hours after exposure 
to an emetogen such as chemotherapy (see Table 
1). Serotonin is released from the enterochromaffin 
cells of the small intestine and activates 5-HT
3
 re-
ceptors on peripheral vagal fibers and central struc-
tures.
 
Delayed emesis occurs after the first 24 hours 
of the exposure to the emetogen and persists up to 
4–6 days. In addition to serotonin, substance P, along 
with other neurotransmitters, appears to have an im-
portant role in the maintenance of acute and delayed 
N/V. 
Anticipatory N/V is defined as a conditioned 
“learned” response, usually occurring when episodes 
of N/V have been inadequately controlled with prior 
exposures. It occurs before, during, or after the expo-
sure to the emetogen, but not at the time emetogen-
related N/V would be expected to occur. 
In this situa-
tion, a variety of stimuli such as odor, sight, or sound 
provoke emesis.
What is the diff erential diagnosis  
of nausea and vomiting?
Michael’s case has helped demonstrate that nausea and 
vomiting is often multifactorial. Fig. 2 details the diff er-
ential diagnosis and etiologies of nausea and vomiting 
as well as providing a helpful mnemonic to quickly re-
call the cartoon:
Fig. 1. Diff erential diagnosis/etiologies of nausea and vomiting (adapted from Dalal et al. 
[1]) 
and a 
quick diff erential diagnosis mnemonic.
Metabolic abnormalities:
e.g. uremia, liver failure,
hypercalcemia
Increased
intracranial pressure
Delayed
chemotherapy-induced
nausea and vomiting
Anxiety
Radiation
therapy
Autonomic
dysfunction
Bowel
obstruction
Peptic ulcer
disease
Other drugs−
e.g. antibiotics, NSAIDs
Opioids
Constipation
Nausea and vomiting
etiology mnemonic
A − Anxiety or anticipatory
V − Vestibular
O − Obstructive
M − Medications and metabolic
A − Infection and inflammatory
T − Toxins
Fig. 1. Diff erential diagnosis/etiologies of nausea and vomiting (adapted from Dalal et al. [1]) 
and a quick diff erential diagnosis mnemonic.

Hematologic Cancer with Nausea and Vomiting
171
What chemotherapy agents cause 
the most problems with nausea     
and vomiting?
How should I assess for nausea   
and vomiting?
Th
  e assessment should include the history and physical 
examination of the patient. When taking the history, ask 
about the characteristics of N/V:
•  Onset (to identify a specifi c trigger)
•  Relationship to eating (postprandial N/V may be 
caused by an obstruction)
•  Medication review (a medication change may 
help)
•  Bowel movement history (are there indications 
for dysfunctional intestines?)
•  Vestibular component (antihistamines might be 
useful)
•  Anxiety or unrelieved pain (often overlooked as 
causes of nausea)
When performing the physical examination, 
watch out for:
•  Cachexia or malnutrition, muscle wasting, de-
creased skin fold thickness (indicators for malab-
sorption)
•  Abdominal distension, increased bowel sounds, 
abdominal masses or ascites (indicators for bowel 
obstruction)
•  Abdominal fullness, including rectal examination 
(constipation due to hypomotility)
•  Papilledema (raised intracranial pressure)
•  Lying and standing blood pressure and Valsalva’s 
maneuver (autonomic dysfunction)
Table 1
Risk  for  emesis  in  the  absence  of  prophylactic  antiemetic  treatment                                                                  
with commonly used chemotherapy drugs [adapted from Perry (2001)]
Drug (Dose)
High Risk (>90%)
Moderate Risk (≥30–90%)
Low Risk (<30%)
Carmustine (>250 mg/m
2
)
Carboplatin
Asparaginase
Cisplatin
Carmustine (<250 mg/m
2
)
Bleomycin
Cyclophosphamide (1500 mg/m
2
) Cisplatin (<50 mg/m
2
)
Cytarabine (<1 g/m
2
)
Dacarbazine (>500 mg/m
2
)
Cyclophosphamide (<1500 mg/m
2
)
Docetaxel
Dactinomycin
Cytarabine (>1 g/m
2
)
Doxorubicin (<20 mg/m
2
)
Lomustine (>60 mg/m
2
)
Doxorubicin
Etoposide (p.o. or i.v.) 
Mechlorethamine
Epirubicin
Fluorouracil (<1 g/m
2
)
Streptozocin
Idarubicin
Gemcitabine
Ifosfamide
Interleukin-2
Irinotecan
Methotrexate (<100 mg/m
2
)
Melphalan
Methotrexate (>100 mg/m
2
)
Mitoxantrone (>12 mg/m
2
)
Mitomycin
Procarbazine
Mitoxantrone (<12 mg/m
2
)
Paclitaxel
Rituximab
Temozolomide
Teniposide
Th
 iotepa
Topotecan
Trastuzumab
Vinblastine
Vincristine

172
Justin Baker et al.
How can nausea and vomiting be 
treated pharmacologically?
Pharmacological treatment of N/V is the mainstay of 
therapy. Table 2 lists frequently used medications to 
treat N/V. Th
  e summary table at the end of this chap-
ter also includes useful treatment algorithms, including 
pharmacological therapy. As with all symptoms, clini-
cians need to frequently reassess the effi
  cacy  of  treat-
ment and anticipate exacerbating factors. Adequate 
treatment and prevention of recurrent or prolonged 
nausea and vomiting are critical.
Can you treat nausea and vomiting 
with nonpharmacological options 
(complementary and alternative 
medicine)?
Nonpharmacological modalities have not yet been ad-
opted and incorporated
 
into evidence-based practice 
guidelines. However, several acupuncture-point stim-
ulation techniques
 
have been examined for treating 
nausea,
 
vomiting, or both. Th
 ese techniques include 
methods that involve
 
needles, electrical stimulation, 
magnets, or acupressure. Evidence supports the use of 
Table 2
Common pharmacological agents used to treat nausea and vomiting (adapted from Policzer and Sobel [3])
Class of Drug
Dose
Comments
Prokinetic Agents
Metoclopramide
5–15 mg before meals and at 
bedtime; s.c./i.v. = p.o.
For nausea and gastric stasis from various causes. Use 
metoclopramide with care; may cause dystonia, which is 
reversible with 1 mg/kg diphenhydramine. Antiemetic 
dosage is greater than prokinetic dosage by 0.1–0.2 mg/kg/
dose. Well tolerated with s.c. administration.
Domperidone
0.3–0.6 mg/kg dose before meals 
and at bedtime to a maximum of 
80 mg/day.
Use domperidone with care; may cause dystonia, which is 
reversible with 1 mg/kg diphenhydramine. 
Antihistamines (Useful for vestibular and gut receptor nausea and vomiting, but relatively contraindicated by constipation 
because they slow the bowels further) 
Diphenhydramine
1 mg/kg/dose p.o. every 4 hours 
to a maximum of 100 mg/dose; 
s.c./i.v. = p.o.
Hydroxyzine
0.5–1 mg/kg/dose every 4 hours 
to a maximum of 600 mg/day; 
s.c./i.v. = p.o.
Promethazine
0.25–1 mg/kg every 4 hours; 
s.c./i.v. = p.o.
Use promethazine with care; can cause dystonia. Risk of 
respiratory arrest in infants
Dopamine Antagonists (Useful for medication and metabolic-related nausea and vomiting. Can cause dystonia, revers-
ible with 1 mg/kg diphenhydramine or 0.02–0.05 mg/kg/dose benztropine to a maximum of 4 mg i.v. Intravenous use can 
cause postural hypotension; therefore i.v. should be given slowly.)
Haloperidol
0.5–5 mg/dose every 8 hours up 
to 30 mg/day; s.c./i.v. = ½ p.o.
Use with care; only some preparations can be given i.v. 
Use dextrose 5% in water to dilute. Well tolerated with s.c. 
administration. 
Chlorpromazine
0.5–1 mg/kg every 8 hours; i.v. 
= p.o.
More sedating. Irritating to tissues with s.c. administra-
tion.
Prochlorperazine 
0.15 mg/kg/dose every 4 hours 
to a maximum of 10 mg/dose; i.v. 
= p.o.
Irritating to tissues with s.c. administration.
Serotonin 5-HT
3
 Receptor Antagonists (Also useful for postoperative nausea and vomiting and as second- or third-line 
agents after other types of antiemetics have demonstrated limited utility)
Ondansetron 
0.15 mg/kg/dose every 6 hours to 
a maximum of 8 mg; i.v. = p.o.
Particularly helpful in chemotherapy-induced nausea and 
vomiting. High cost may preclude its use.

Hematologic Cancer with Nausea and Vomiting
173
electroacupuncture by clinicians
 
competent in its ad-
ministration for chemotherapy-induced nausea.
 
Other 
modalities have not been well studied, but details are 
provided for a comprehensive analysis. Table 3 provides 
details of all nonpharmacological and complementary 
and alternative modalities and gives examples of po-
tential antiemetic benefi ts.
Class of Drug
Dose
Comments
Benzodiazepines
Diazepam 
0.05–0.2 mg/kg dose every 6 
hours; i.v. = p.o.
Helpful for anticipatory nausea and vomiting. Diazepam 
stings during i.v. administration; use a large vein and dilute 
solution. For patients younger than 5 years, max. dosage is 
5 mg/dose. For patients older than 5 years, max. dosage is 
10 mg/dose.
Lorazepam
0.03–0.05 mg/kg dose every 5 
hours to a maximum 4 mg/dose; 
i.v. = p.o./s.l.
Corticosteroids
Dexamethasone 
6–10 mg loading dose, then 2–4 
mg 2–4 times a day for mainte-
nance; i.m./i.v. = p.o.
Helpful for hepatic capsular distention, anorexia, and 
increased intracranial pressure. Can have long-term side 
eff ects. If the patient weighs less than 10 kg, 1 mg/kg 
loading dose, and then 0.1–0.2 mg/kg 2–4 times a day for 
maintenance. Agonist eff ect when used in combination 
with serotonin antagonists.
Prednisone
1.5 mg dexamethasone = 10 mg 
prednisone
Cannabinoids
Dronabinol
2.5 mg twice a day (for adults 
only) to a max of 20 mg/day
Can cause dysphoria, drowsiness, or hallucinations. Ap-
petite stimulant.
Other Anticholinergics
Scopolamine
Transdermal preparation: 0.5 mg 
changed every 72 hours; i.v./s.c.: 
0.006 mg/kg every 6 hours
Helpful for motion- or movement-related nausea and 
vomiting. Well-tolerated by s.c. tissues. Often causes dry 
mouth and blurred vision, and sometimes causes confu-
sion.
Table 3
Nonpharmacologic and complementary and alternative modalities used to treat nausea and vomiting (adapted from the 
National Comprehensive Cancer Network 2005)
Modality
Defi nition
Examples with Benefi t in Nausea 
and Vomiting
Massage therapy
Group of systematic and scientifi c manipulations of 
body tissues best performed with the hands to aff ect 
the nervous and muscular systems and general circula-
tion
Reiki, therapeutic touch
Mind-body, other 
relaxation techniques
Methods that emphasize mind-body interactions with 
intended benefi ts that include relaxation and emo-
tional well-being
Meditation—transcendental and 
mindfulness, yoga, prayer, guided 
imagery, relaxation training
Music therapy
Th
  e use of music to help treat neurological, mental, 
and behavioral disorders
Eff ective in postoperative nausea/
vomiting 
Acupuncture therapy
Treatment of symptoms by inserting needles along 
specifi c pathways
Acupuncture or acupressure at the 
Nei Guan or P6 point
Dietary supplements
Products in capsule, tablet, liquid, or dried form, in-
cluding vitamins, proteins, herbs, and other over-the-
counter substances intended for decreasing nausea 
and vomiting
Ginger root, huangqi decoctions, 
aromatherapy 

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Justin Baker et al.
What are the side eff ects                     
of therapy?
All medications have a primary eff ect and side eff ects. 
Antiemetics should be chosen mainly on the basis of the 
etiology of the N/V and the mechanism of the medica-
tion. Side eff ects may hinder the ability to use certain 
drugs, however. Table 4 lists common side eff ects of an-
tiemetics by the category of drug.
Table 4
Side eff ects of medications commonly used to treat nausea and vomiting
Medication Adverse 
Eff ects*
Antihistamines
Diphenhydramine
Hydroxyzine
Most common: sedation, dry mouth, constipation.
Less common: confusion, blurred vision, urinary retention.
Belladonna alkaloid
Scopolamine
Most common: dry mouth, drowsiness, impaired eye accommodation.
Rare: disorientation, memory disturbances, dizziness, hallucinations.
Benzamides
Benzquinamide
Metoclopramide
Trimethobenzamide
Most common: sedation, restlessness, diarrhoea (metoclopramide), agitation, 
CNS depression.
Less common: extrapyramidal eff ects (more frequent with higher doses), 
hypotension, neuroleptic syndrome, supraventricular tachycardia (with i.v. 
administration).
Benzodiazepines
Lorazepam 
Most common: sedation, amnesia.
Rare: respiratory depression, ataxia, blurred vision, hallucinations, paradoxical 
reactions (weeping, emotional reactions).
Butyrophenones
Droperidol
Haloperidol
Most common: sedation, hypotension, tachycardia.
Less common: extrapyramidal eff ects, dizziness, increase in blood pressure, 
chills, hallucinations.
Cannabinoids
Dronabinol 
Most common: drowsiness, euphoria, somnolence, vasodilation, vision dif-
fi culties, abnormal thinking, dysphoria.
Less common: diarrhea, fl ushing, tremor, myalgia.
Corticosteroids
Dexamethasone
Methylprednisolone
Most common: gastrointestinal upset, anxiety, insomnia.
Less common: hyperglycemia, myopathies, osteonecrosis, facial fl ushing, 
mood changes, perineal itching or burning.
Phenothiazines
Prochlorperazine
Promethazine
Chlorpromazine
Th
 iethylperazine
Most common: sedation, lethargy, skin sensitization.
Less common: cardiovascular eff ects, extrapyramidal eff ects, cholestatic jaun-
dice, hyperprolactinemia.
Rare: neuroleptic syndrome, hematological abnormalities.
5-HT
3
-receptor antagonists
Granisetron
Dolasetron
Ondansetron
Most common: headache, asymptomatic prolongation of electrocardiographic 
interval.
Less common: constipation, asthenia, somnolence, diarrhea, fever, tremor or 
twitching, ataxia, lightheadedness, dizziness, nervousness, thirst, muscle pain, 
warm or fl ushing sensation on i.v. administration.
Rare: transient elevations in serum transaminases.
* Most common; >10%; less common, 1%–10%; rare, <1%. Based on U.S. Food and Drug Administration-
approved labeling and generalized to the drug class.

Hematologic Cancer with Nausea and Vomiting
175
Pearls of wisdom
Treatment algorithms (adapted from Policzer and Sobel 
[3]) are shown in Table 5.
References
[1]  Dalal S, Palat G, Bruera E. Chronic nausea and vomiting. In: Berger 
AM, Shuster JL, Von Roenn, Jamie H, editors. Principles and practice 
of palliative care and supportive oncology, 3rd edition. New York: Lip-
pincott Williams & Wilkins; 2007.
[2]  Naeim A, Dy SM, Lorenz KA, Sanati H, Walling A, Asch SM. Evidence-
based recommendations for cancer nausea and vomiting. J Clin Oncol 
2008;26:3903–10.
[3]  Policzer JS, Sobel J. Management of selected nonpain symptoms of life-
limiting illness. Hospice and palliative care training for physicians—a 
self-study program, 3rd edition, vol. 4. Glenview, IL: American Acad-
emy of Hospice and Palliative Medicine; 2008.
Table 5
Treatment algorithms
Cause
Symptoms
Treatment Alternatives
Cortical
CNS tumor/meningeal irritation
Focal neurological signs or mental status 
changes
Corticosteroids
Consider palliative radiation
Increased intracranial pressure
Projectile vomiting and headache
Corticosteroids
Anxiety or psychogenic symp-
toms
Anticipatory nausea, conditioned responses
Counseling
Relaxation techniques
Benzodiazepines
Uncontrolled pain
Pain and nausea
Increase pain medications
Use adjuvants
Vestibular
Vestibular disease
Vertigo or vomiting after head motion
Antihistamines (meclizine)
Middle-ear infections
Ear pain or bulging tympanic membrane
Antibiotic therapy and other supportive 
care
Motion sickness
Travel-related nausea
Anticholinergics (scopolamine)
Chemoreceptor Trigger Zone
Medications
Nausea worse after medication dosage or exac-
erbated after increasing dose
Decrease dose or discontinue medication
Metabolic (renal or liver failure)
Increased blood urea nitrogen (BUN), creati-
nine, bilirubin, etc.
Dopamine antagonist
Hypercalcemia
Somnolence, delirium, high calcium
Hydration
Corticosteroids
Bisphosphonates
Gastrointestinal Tract
Irritation from medications
Use of nonsteroidal anti-infl ammatory drugs 
(NSAIDs), iron, alcohol, antibiotics
Discontinue drug if possible
Add histamine (H
2
) blocker, proton pump 
inhibitor, or misoprostol
Tumor infi ltration or infection
Evidence of abdominal tumor, candida esopha-
gitis, colitis
Antihistamines
Treat infection
Anticholinergics
Constipation or impaction
Abdominal distension, no bowel movement for 
many days
Laxatives
Manual disimpaction
Enema
Obstruction by tumor or poor 
motility
Constipation unrelieved by treatment
Prokinetic agents
Malignant bowel obstruction
Severe pain, abdominal distension, visible 
peristalsis
Analgesics (opioids)
Anticholinergics
Dopamine antagonists
Corticosteroids
Consider octreotides