CONTEMPO UPDATES
LINKING EVIDENCE AND EXPERIENCE
Cancer Pain
Eduardo Bruera, MD
Hak Nam Kim, MD
A
PPROXIMATELY 1 IN 3 INDIVIDU-
als in the developed world will
be diagnosed with cancer and
half of those patients will die
of progressive disease.1 More than 80%
of patients with cancer develop pain be-
fore death.2 Pain is consistently one of
the most feared consequences of cancer
for both patients and families. Major im-
provements in the management of can-
cer pain in recent years include better as-
sessment of pain, recognition and
treatment of opioid-induced neurotox-
icity, and the emerging use of opioid ro-
tation and of methadone.
Assessment
In approximately two thirds of patients
with cancer, pain is directly related to the
presence of primary or metastatic dis-
ease3; another third of patients with can-
cer develop pain syndromes because of
treatment, including sequelae of sur-
gery, radiation, or chemotherapy, and
other related causes such as osteoporo-
sis, immobility, and infections.3 An un-
derstanding of the mechanism of the pain
may be helpful in planning for optimal
therapy. For example, incidental pain
(due to voluntary or involuntary move-
ment) and neuropathic pain (due to cen-
tral or peripheral nervous system de-
struction or nerve compression) usually
respond poorly to opioid analgesics4 and
require adjuvant analgesia.
Pain intensity can be assessed accu-
rately by using simple validated meth-
ods such as 0 to 10 numerical scales,
verbal descriptors, pictorial scales
CME available online at
www.jama.com
2476 JAMA, November 12, 2003—Vol 290, No. 18 (Reprinted)
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/25/2015
CLINICIAN’S CORNER
(faces, circles of different colors), or vi-
sual analog scales (FIGURE 1).4-7 Dis-
playing this information in the pa-
tient’s chart makes his or her symptom
distress visible to caregivers, allowing
for better evaluation and monitoring of
the quality of care.5
The rating of pain intensity by a given
patient is not solely a reflection of the
level of nociception produced by the
painful tumor. The expression of pain
intensity should always be considered
a multidimensional construct and not
a direct representation of somatosen-
sory cortex impact by afferent stimuli
(FIGURE 2). Pain intensity reported by
a patient represents the expression of
pain that should be used for monitor-
ing and adjusting treatment. Two pa-
tients with a similar cancer location may
experience different levels of nocicep-
tion from the tumor itself, different lev-
els of somatosensory cortex activity, and
different expression of pain because of
the influence of culture, beliefs, mood,
or delirium.5 Some patients have scores
of expressed pain that are consistently
high relative to apparent pathophysi-
ology. In these cases, physicians should
try to identify which factors are con-
tributing to pain expression.5
Patients with cancer pain present with
a variety of other symptoms, including
fatigue, anorexia, cachexia, chronic nau-
sea, dyspnea, anxiety, and depression.
Any of these symptoms can affect the ex-
pression of pain and may, in turn, be ag-
gravated by the pain or its treatment.
Management
Cancer pain can be controlled with
simple treatments in more than 80% of
cases.8 In the remaining 20%, it is im-
portant to use a multidimensional ap-
proach that includes a careful reassess-
ment of the pain syndrome and use of
©2003 American Medical Association. All rights reserved.
second line agents and/or nonpharma-
cological interventions.8
Pharmacological Management
Mild pain can be treated with acetami-
nophen or nonsteroidal anti-inflamma-
tory drugs.9 Moderate or more intense
pain often responds to codeine, hydro-
codone, and tramadol, which are mild
opioid agonists. Tramadol is also a nor-
epinephrine and selective serotonin re-
uptake inhibitor and has the advantage
of additional nonopioid central effects.
A disadvantage of these drugs is that dose
escalation potential is very low because
of unacceptable toxicity. Partial ago-
nists and opioid agonists/antagonists
such as buprenorphine hydrochloride,
nalbuphine hydrochloride, or butorpha-
nol are of limited value. They may cause
opioid withdrawal when given to pa-
tients who have already been exposed to
a significant dose of opioid agonists.10
Meperidine and propoxyphene are best
avoided because they can accumulate in
patients with decreased renal function or
dehydration10 and cause neurotoxicity.
For severe pain, potent opioid agents in-
cluding morphine (the current crite-
rion standard), hydromorphone, oxy-
codone, fentanyl, and methadone should
be used.
There is little difference in efficacy or
adverse effects between these opioid ago-
nists. Patients with cancer pain who have
not responded to mild opioids or who
have rapidly progressive severe pain at
onset should be started on a potent fast-
Author Affiliation: Department of Palliative Care and
Rehabilitation Medicine, University of Texas M. D.
Anderson Cancer Center, Houston, Tex.
Corresponding Author and Reprints: Eduardo Bruera,
MD, Department of Palliative Care and Rehabilita-
tion Medicine, Unit 008, University of Texas M. D.
Anderson Cancer Center, 1515 Holcombe Blvd, Hous-
ton, TX 77030 (e-mail: ebruera@mdanderson.org).
Contempo Updates Section Editor: Catherine Meyer,
MD, Fishbein Fellow.
 CANCER PAIN

acting opioid, which should be given
around the clock; patients should be al-
lowed to take extra doses as needed.10
Patients with severe pain may need rapid
titration of a potent opioid given as a
continuous intravenous infusion. In
most cases, this approach will control the
pain within 24 to 48 hours.
Once patients have achieved good
pain control, it is usually possible to
maintain analgesia by using slow-
release opioids, such as morphine ev-
ery 12 or 24 hours, oxycodone every
12 hours, or transdermal fentanyl ev-
ery 3 days. These drugs are easier for
Bisphosphonates can decrease pain
intensity as well as bone fractures, hy-
percalcemia, and the need for radiation
therapy in patients with bone metasta-
ses.17,18 In addition, in selected cases in
which incidental pain can be antici-
pated before a planned activity or pro-
cedure, such as bathing, dressing, or
Figure 1. Edmonton Symptom Assessment System
Date 11 11 11
11 12
10
Pain
wound debridement, oral transmuco-
sal fentanyl may provide rapid short-
acting analgesia.19 Nausea will occur in
the majority of patients but usually with
rapid development of tolerance. Meto-
clopramide and other promotable agents
are effective in the prevention and man-
agement of this problem.20
11 11 11 11
13 14 15 16 17
Worst Possible Pain

patients to use because of reduced 0 No Pain

frequency of dosing but they are ex- 10 Worst Possible Tiredness
pensive. All patients receiving slow-
release opioids should also be given Tiredness
prescriptions for immediate-release 0 Not Tired
opioids that can be used for break-
10 Worst Possible Nausea
through pain.
Approximately 80% of patients with Nausea
cancer will not be able to take oral opi- Not Nauseated
0
oids for some period before death.11 Pa-
10 Worst Possible Depression
tients who already have an intrave-
nous line can be given a continuous Depression
infusion of morphine, hydromor-
0 Not Depressed
phone, fentanyl, or oxycodone, or in-
10 Worst Possible Anxiety
termittent injections of methadone. The
subcutaneous route, using an indwell- Anxiety
ing butterfly needle, is simpler, more
0 Not Anxious
comfortable, and less expensive and
should be used whenever possible.11 10 Worst Possible Drowsiness
Methadone is the only opioid re- Drowsiness
ported to produce irritation when ad-
0 Not Drowsy
ministered subcutaneously.
Patients and families should be edu- 10 Worst Possible Appetite
cated about the most common adverse Appetite
effects of opioids to prevent unwar-
ranted fears and noncompliance. Seda- 0 Best Appetite

tion occurs in the majority of patients but 10 Worst Possible Feeling of Well-being
there is rapid development of tolerance Well-being
to this symptom, usually within 3 to 7
days.12 In less than 10% of patients, the 0 Best Feeling of Well-being
opioid dose required for analgesia causes 10 Worst Possible Shortness of Breath
chronic sedation.13 In these patients, a
Shortness of Breath
trial of opioid rotation or the use of psy-
chostimulants, such as methylpheni- 0 No Shortness of Breath
date13,14 or donepezil,15 may be useful. In 10 Worst Possible
these cases, other therapies should also
Other Problem
be considered in order to decrease opi-
oid requirement. Radiation therapy is 0 None
highly effective in reducing pain, par-
ticularly in patients with bone pain.16 Adapted from the Edmonton Symptom Assessment System scale.7

©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, November 12, 2003—Vol 290, No. 18 2477

Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/25/2015

 CANCER PAIN

Constipation occurs in the majority methylnaltrexone are being tested in recommended for the management of
of patients receiving opioids and does ongoing clinical trials and may be- these symptoms.22
not improve over time. This symptom come useful additions to laxatives.21 Opioid rotation is a treatment approach
is underdiagnosed and can result in se- Opioid-induced neurotoxicity (BOX) that has gained acceptance during the
rious complications, such as anorexia, is a recently recognized syndrome. It oc- past 5 years; it usually involves stop-
vomiting, abdominal pain, and, rarely, curs in patients receiving high-dose or ping the initial opioid abruptly and
abdominal perforation. Contact cathar- prolonged opioid administration and in replacing it with an equivalent dose of
tic laxatives such as senna or dan- patients who have decreased renal func- an alternative opioid.22 Commonly used
thron, usually combined with stool soft- tion or previous borderline cognition. equianalgesic tables were not devel-
eners such as docusate, should be The features of opioid-induced neuro- oped specifically as guidelines for use
started in all patients receiving regu- toxicity are mostly excitatory and in- with patients receiving chronic high-
lar opioid analgesics, unless there are clude delirium, agitation, myoclonus, dose opioid therapy who require opioid
major contraindications.21 Peripher- and hyperalgesia. Hydration, dose re- rotation.23 Large interindividual varia-
ally acting opioid antagonists such as duction, and opioid rotation have been tion in dose ratios will occasionally occur;
therefore, in most cases, it is appropri-
ate to begin the new opioid regimen at a
Figure 2. Steps Involved in the Expression of Cancer Pain
daily dose 30% to 50% lower than the
equianalgesic recommendation and then
Painful Stimuli slowly increase the dose of the new opi-
Primary or Metastatic Tumor oid until adequate analgesia is achieved.
Treatment-Related Stimuli Inrecentyears,methadonehasbecome
an attractive analgesic option for opioid
rotation.24 This synthetic opioid agonist
Nociception
has excellent oral bioavailability and no
(Pain Receptors) knownactiveopioidmetabolites.Itisalso
significantlylessexpensivethanotheropi-
Descending oids. Its main disadvantages are its long
Inhibitory Pathways and variable elimination half-life leading
Endorphins to potential accumulation and adverse ef-
fects in some patients, and the difficulty
Perception in establishing equianalgesic dose ratios
(Somatosensory Cortex) during opioid rotation. The dose ratio
of most opioids is relatively fixed over a
Psychosocial Factors wide range of doses. For example, the
Culture morphine/hydromorphoneratioformost
Beliefs patientsisapproximately5(10mgofmor-
phine=2 mg of hydromorphone, 100
Mental Status mg=20 mg). In the case of methadone,
Depression this ratio is highly variable, ranging from
Anxiety Pain Cancer less than 5 in patients receiving less than
Delirium Treatment Treatment
100 mg of morphine per day to more than
20 in patients receiving more than 1000
Cancer and mg of morphine per day.23-25 Once a pa-
Treatment-Related tient’streatmentrotationwithmethadone
Symptoms
Fatigue
has been successful, dose titration and
Anorexia monitoring is the same as with other opi-
Cachexia oidanalgesics.Anaddedadvantageofthis
Nausea
Dyspnea
drug is its availablility as an elixir. The
elixir is long-acting and can be admin-
istered via tube (eg, in patients with head
Expression of Pain and neck cancer).

Adjuvant Drugs
Many factors contribute to the overall expression of pain; those that diminish pain intensity are indicated by In some patients, opioid titration up to
blue lines.
the level of dose-limiting adverse ef-
2478 JAMA, November 12, 2003—Vol 290, No. 18 (Reprinted) ©2003 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/25/2015


fects does not provide sufficient analge-
sia.5,26 Patients with neuropathic pain,
which usually has poor opioid respon-
siveness, may fall into this category. In
these cases, adjuvant drugs can provide
added pain relief. Adjuvant drugs are
agents with no intrinsic analgesic effect
that are capable of producing analgesia
in certain situations, as when given with
opioids. It is important to optimally ti-
trate the opioid analgesic and attempt to
manage potential dose-limiting adverse
effects such as sedation, nausea, or con-
stipation before starting an adjuvant
drug. Anticonvulsants (gabapentin) and
antidepressants (desipramine and nor-
triptyline) are examples of drugs that can
be used to enhance analgesia.27 Most ad-
juvant analgesics are centrally acting
agents and may therefore cause seda-
tion, decreased cognition, and fatigue.
Corticosteroids can act as effective ad-
juvant analgesics by reducing peritu-
moral edema in brain, liver, or thoracic
tumors. Antibiotics can be helpful for
treatment of sudden increases in pain re-
lated to ulceration of head and neck or
pelvic tumors.
REFERENCES
1. World Health Organization. The World Health Re-
port 1996: Fighting Disease, Fostering Develop-
ment, Executive Summary. Geneva, Switzerland: World
Health Organization; 1996.
2. Foley KM. Controlling cancer pain. Hosp Pract (Off
Ed). 2000;35:101-108, 111-112.
3. Cherney IN. Cancer pain: principle of assessment
and syndromes. In: Berger AM, Portenoy RK, Weiss-
man DE, eds. Principle and Practice of Palliative Care
and Supportive Oncology. 2nd ed. Philadelphia, Pa:
Lippincott William & Wilkins; 2002:3-52.
4. Bruera E, Schoeller T, Wenk R, et al. A prospective
multicenter assessment of the Edmonton staging sys-
tem for cancer pain. J Pain Symptom Manage. 1995;
10:348-355.
5. Bruera E, Neumann C. History and clinical exami-
nation of the cancer pain patient: assessment and mea-
surement. In: Rice A, Warfield C, Justin D, Eccleston
C, eds. Clinical Pain Management Cancer Pain. New
York, NY: Oxford University Press; 2003:63-71.
6. Bruera E, Neumann CM. Respective limits of pal-
liative care and oncology in the supportive care of can-
cer patients. Support Care Cancer. 1999;7:321-327.
7. Guidelines for using the Edmonton Symptom As-
sessment System (ESAS). Available at: http://
www.palliative.org/PC/ClinicalInfo/Assessment
Tools?easa.pdf. Accessibility verified October 24, 2003.
8. Zech DFJ, Grond S, Lynch J, et al. Validation of the
World Health Organization guidelines for cancer pain re-
lief: a 10-year prospective study. Pain. 1995;63:65-76.
9. Rawlins MD. Non-opioid analgesics. In: Doyle D,
Hanks GW, MacDonald N, eds. Palliative Medicine.
2nd ed. New York, NY: Oxford University Press; 1998:
355-361.
10. Ripamonti C. Pharmacology of opioid analgesia:
©2003 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/25/2015
Nonpharmacological Treatment
Patients who have no improvement in
their pain intensity after appropriate use
of multiple opioid trials, use of adjuvant
drugs, and appropriate monitoring of
adverse effects may be considered for
nonpharmacological interventions. Neu-
rosurgical ablative procedures, such as
cordotomy, myelotomy, or thala-
motomy, have been available for 40 years.
In recent years, augmentative therapies
such as intraventricular opioid infusion
or deep brain stimulation have been used
more frequently.26 Anesthesia proce-
dures that have been tried include the epi-
dural or intraspinal infusion of opioids
with or without local anesthetics.27 All
of these interventions are complex and
expensive, and their role is not cur-
rently supported by large randomized
controlled trials; however, they can be
useful in selected intractable cases.
Conclusion
Cancer pain can be successfully con-
trolled in most patients with a number
of safe and relatively inexpensive drugs.
In recent years, there have been some
clinical principles. In: Bruera E, Portenoy RK, eds. Can-
cer Pain. Cambridge, England: Cambridge University
Press; 2003:124-149.
11. Ripamonti C, Zecca E, De Conno F. Pharmaco-
logical treatment of cancer pain: alternative routes of
opioid administration. Tumori. 1998;84:289-300.
12. Bruera E, Macmillan K, Hanson J, MacDonald RN.
The cognitive effects of the administration of nar-
cotic analgesics in patients with cancer pain. Pain. 1989;
39:13-16.
13. Bruera E, Brenneis C, Paterson AHG, MacDonald
RN. Use of methylphenidate as an adjuvant to nar-
cotic analgesics in patients with advanced cancer.
J Pain Symptom Manage. 1989;4:3-6.
14. Bruera E, Driver L, Barnes EA, et al. Patient-
controlled methylphenidate for the management of
fatigue in patients with advanced cancer: a prelimi-
nary report. J Clin Oncol. In press.
15. Bruera E, Strasser F, Shen L, et al. The effect of
donepezil on sedation and other symptoms in pa-
tients receiving opioids for cancer pain: a pilot study.
J Pain Symptom Manage. In press.
16. Centeno C, Gonzalez C. Radiotherapy for pallia-
tive of symptoms. In: Fisch H, Bruera E. Handbook of
Advanced Cancer Care. Cambridge, England: Cam-
bridge University Press; 2003:27-39.
17. Pereira J. Management of bone pain. In: Por-
tenoy R, Bruera E, eds. Topics in Palliative Care. Vol
3. New York, NY: Oxford University Press; 1998:79.
18. Ross JR, Saunders Y, Edmonds PM, et al. System-
atic review of role of bisphosphonates on skeletal mor-
bidity in metastatic cancer. BMJ. 2003;327:469-
472.
19. Coluzzi PH, Schwartzberg L, Conroy JD, et al.
Breakthrough cancer pain: a randomized trial com-
(Reprinted) JAMA, November 12, 2003—Vol 290, No. 18 2479
CANCER PAIN
Box. Opioid Adverse Effects
Sedation
Nausea
Constipation
Respiratory depression
Other (pruritus, anaphylaxis, sweat-
ing, urinary retention)
Opioid-induced neurotoxicity: cog-
nitive failure, hallucinations/
delirium, myoclonus/grand mal
seizures, hyperalgesia/allodynia,
severe sedation/coma
advances in our abilities to manage can-
cer pain. We now recognize that opi-
oids can produce neurotoxicity. We are
using methadone more readily and have
learned that opioid rotation can help
some patients. Physicians can further en-
hance the well-being of patients with
cancer pain if they conduct a careful as-
sessment of the pain syndrome, fre-
quently monitor adverse effects of drugs,
and maintain excellent communica-
tion with the patient and family.
paring oral transmucosal fentanyl citrate (OTFC) and
morphine sulfate immediate release (MSIR). Pain. 2001;
91:123-130.
20. Bruera E, Seifert L, Watanabe S, et al. Chronic nau-
sea in advanced cancer patients: a retrospective as-
sessment of a metoclopramide-based antiemetic regi-
men. J Pain Symptom Manage. 1996;11:147-153.
21. Mancini I, Bruera E. Constipation. In: Ripamonti
C, Bruera E, eds. Gastrointestinal Symptoms in Ad-
vanced Cancer Patient. New York, NY: Oxford Uni-
versity Press; 2002:193-206.
22. Strasser F, Bruera E. Side effects of opioid anal-
gesia. In: Bruera E, Portenoy RK, eds. Cancer Pain.
Cambridge, England: Cambridge University Press;
2003. In press.
23. Bruera E, Pereira J, Watanabe S, et al. Opioid ro-
tation in patients with cancer pain: a retrospective com-
parison of dose ratios between methadone, hydromor-
phone, and morphine. Cancer. 1996;78:852-857.
24. Bruera E, Sweeney C. Methadone use in cancer
patients with pain: a review. J Palliat Med. 2002;5:
127-138.
25. Mercadante S, Portenoy RK. Opioid poorly-
responsive cancer pain, part 3: clinical strategies to im-
prove opioid responsiveness. J Pain Symptom Man-
age. 2001;21:338-354.
26. Hassenbusch SJ, Johns L. Neurosurgical tech-
niques in the management of cancer pain. In: Bruera
E, Portenoy R, eds. Cancer Pain. Cambridge, En-
gland: Cambridge University Press; 2003:261-276.
27. Smith TJ, Staats PS, Deer T, et al. Randomized clini-
cal trial of an implantable drug delivery system com-
pared with comprehensive medical management for
refractory cancer pain: impact on pain, drug-related tox-
icity, and survival. J Clin Oncol. 2002;20:4040-4049.