PERSPECTIVES ON CARE
AT THE CLOSE OF LIFE
Managing an Acute Pain Crisis
in a Patient With Advanced Cancer
“This Is as Much of a Crisis as a Code”
Natalie Moryl, MD
Nessa Coyle, NP, PhD
Kathleen M. Foley, MD
THE PATIENT’S STORY
Mr X is a 33-year-old man with a 4-year history of meta-
static mucinous adenocarcinoma of the appendix. Over the
course of his illness, Mr X completed several cycles of che-
motherapy and had several percutaneous draining osto-
mies for small-bowel obstruction due to peritoneal carci-
nomatosis. His most recent admissions were triggered by
protracted nausea and vomiting and recurrent small-bowel
obstructions associated with increasing abdominal pain.
In recent months, Mr X’s overall care had been managed
by his medical oncologist and the anesthesia pain service.
In addition, on the admission prior to this, he had been briefly
seen by a palliative care physician. His wife reported that
he had been “close to death” on several previous admis-
sions. Mr X and his family were aware of the extent of his
disease but wanted aggressive life-prolonging treatment to
continue, including cardiopulmonary resuscitation. Mr X’s
baseline chronic abdominal pain had nociceptive, visceral,
and neuropathic features and had been difficult to manage.
After a variety of opioid trials, he had finally obtained some
analgesia on escalating doses of intravenous (IV) metha-
done. His methadone dose at home after his last admission
was 800 mg over 24 hours (200 mg IV every 6 hours), with
his wife administering each 200-mg dose over a 20- to 30-
minute period. A visiting nurse service and a home care in-
fusion company oversaw his methadone administration.
One day before his final hospital admission, Mr X under-
went a celiac plexus block in an attempt to improve his pain
relief and decrease his opioid requirements. Two hours later
he developed fever and severe abdominal pain, self-rated as
“15 out of 10” on a 0-to-10 scale. The patient’s unrelieved
pain and the visiting nurse’s concern that the methadone
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CLINICIAN’S CORNER
The assessment and management of an acute pain crisis in
the setting of advanced illness is challenging. Using the
case of Mr X, a 33-year-old man with advanced metastatic
mucinous adenocarcinoma of the appendix and “15 out of
10” pain, we explore the issues of acute pain and its man-
agement. We define a pain crisis as an event in which the
patient reports pain that is severe, uncontrolled, and caus-
ing distress for the patient, family members, or both. Our
management strategy focuses on making a pain diagno-
sis, differentiating reversible from intractable causes of pain,
and making decisions about further workup; selecting the
opioid and monitoring and treating opioid adverse effects;
titrating and rotating opioid and coanalgesics; consulting
experts to treat a pain crisis as quickly as possible to pre-
vent unnecessary suffering; and co-opting the available insti-
tutional resources. The timely intervention of a palliative
care team and its expertise can provide the staff, patients,
and their families the benefit of an interdisciplinary approach
and help the patients address goals of care; understand the
benefits and risks of treatment decisions; and meet the psy-
chological, social, and existential needs of the patient and
the family commonly seen in this setting.
JAMA. 2008;299(12):1457-1467 www.jama.com
regimen was contraindicated because of the finding of a QTc
prolongation on an electrocardiogram with the conse-
quent potential for an arrhythmia led to the decision to bring
the patient back to the hospital.
Author Affiliations: Department of Neurology, Pain and Palliative Care Service,
Memorial Sloan-Kettering Cancer Center, New York, New York.
Corresponding Author: Kathleen M. Foley, MD, Weill Medical College of Cornell
University, and Department of Neurology, Pain and Palliative Care Service, Me-
morial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021 (foleyk
@mskcc.org).
Perspectives on Care at the Close of Life is produced and edited at the University
of California, San Francisco, by Stephen J. McPhee, MD, Michael W. Rabow, MD,
and Steven Z. Pantilat, MD; Amy J. Markowitz, JD, is managing editor.
Perspectives on Care at the Close of Life Section Editor: Margaret A. Winker, MD,
Deputy Editor.
(Reprinted with Corrections) JAMA, March 26, 2008—Vol 299, No. 12 1457
 PERSPECTIVES ON CARE AT THE CLOSE OF LIFE
Upon his arrival at the hospital, the patient’s tempera-
ture was 40.0°C, his blood pressure was 98/40 mm Hg, his
heart rate was 116/min, and his respiratory rate was 34/
min. When examined by Dr P, the attending physician on
the medicine team, he was sitting up in bed in acute dis-
tress. He was cachectic and jaundiced and complained of
severe abdominal pain. His abdominal examination re-
vealed diffuse tenderness to palpation with rebound and
guarding. There was pus draining through the skin sites of
previous percutaneous draining ostomies.
The initial impression was that Mr X was in an acute pain
crisis superimposed on chronic abdominal pain. The pain
exacerbation was thought to be associated with acute peri-
tonitis or bowel perforation due to the progressive meta-
static disease or the recent celiac plexus block. The main
priority of the medical team was pain crisis management and
reestablishing the goals of care in the setting of the rapid
worsening of the patient’s condition. Despite the severity
of his pain, Mr X was alert and oriented with clear capacity
to engage in decision making about his care.
The medical team, in consultation with the anesthesia pain
service, decided to transfer Mr X to the intensive care unit
(ICU) because of plans to control his pain with high-dose
IV opioids and ketamine. This would require a level of ob-
servation and monitoring not available on a medical ward.
Mr X’s electrocardiogram again showed a prolonged QTc
interval. Because of the possibility that this was associated
with the high dose of parenteral methadone, the decision
was made to discontinue the methadone and rotate to IV
hydromorphone. Hydromorphone infusion was titrated from
30 mg/h to 80 mg/h with IV boluses of 80 mg every 10 min-
utes over the early morning hours without any improve-
ment in his pain. He was also given a racemic ketamine in-
fusion titrated up to 7 mg/h. After almost 5 g of
hydromorphone in a 10- to 12-hour period, the patient re-
ported no improvement in pain.
Dr S, the palliative care consultant, met with the family
and discussed the risks of restarting IV methadone despite
QTc interval prolongation. Mr X and his wife acknowl-
edged that he was dying, requested use of any medications
necessary to stop his pain, and declined further life-
prolonging measures such as cardiopulmonary resuscita-
tion. Pain relief, other symptom control, and facilitating the
opportunity for him to say good-bye to family and friends
became the focus of his care. The immediate goal was to man-
age the acute pain crisis as quickly as possible. The hydro-
morphone was discontinued and the methadone was re-
started with IV boluses of 40 mg every 15 minutes until pain
relief was obtained. It had taken almost 12 hours to reduce
his pain from 15 to 2 on a scale of 0 to 10. Within several
hours, a total dose of 1.59 g of methadone was adminis-
tered, and Mr X reported minimal and adequately con-
trolled pain of 2 on a 0-to-10 scale. His mental status re-
mained intact. His wife stayed with him throughout. During
this period, the ICU staff created a private environment for
1458 JAMA, March 26, 2008—Vol 299, No. 12 (Reprinted with Corrections)
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Mr X and his family, as homelike as possible, in which all
of the monitoring necessary to manage his pain and other
symptoms was available. As he became more comfortable,
his methadone dose was stabilized, and Mr X made tele-
phone calls to say good-bye to family and friends.
Over the ensuing hours, his pain again started to esca-
late and the doses of IV methadone were titrated up. Even-
tually, he became sedated without evidence of distress, but
he developed myoclonic jerks. He was given a 60-mg dose
of dantrolene intravenously and the myoclonus resolved.
Approximately 36 hours after admission, Mr X died peace-
fully. His wife, their 2 dogs, and several family members and
friends were present.
Dr P and Dr S were interviewed by a Perspectives editor
in January 2005.
PERSPECTIVES
DR P: I think as a primary medical team, we were becoming
uncomfortable with the dosage and the amount of pain medi-
cation the patient was requiring . . .
DR S: The patient looked ashen and stressed. He was just
holding his belly and he looked incredibly uncomfortable. He
was sweating and basically telling us that he really, really
wanted us to do whatever it took to get his pain under control.
Assessment and Management of an Acute Pain Crisis
The assessment and management of an acute pain crisis in
the setting of advanced illness are challenging.1,2 Using Mr
X’s case, we outline a management strategy that focuses on
(1) making a pain diagnosis, differentiating reversible from
intractable causes of pain and making decisions about fur-
ther workup, (2) selecting the opioid and monitoring and
treating adverse opioid effects, (3) titrating and rotating opi-
oids and coanalgesics, (4) consulting experts to treat a pain
crisis as quickly as possible to prevent unnecessary suffer-
ing, and (5) identifying and co-opting the available institu-
tional resources.
Definition of a Pain Crisis
We define a pain crisis as an event in which the patient re-
ports severe, uncontrolled pain that is causing the patient,
family, or both severe distress. The pain may be acute in on-
set or may have progressed gradually to an intolerable thresh-
old (as determined by the patient), but requires immediate
intervention. National Comprehensive Cancer Network pain
management guidelines identify a pain emergency as an event
in which patients have severe pain (a numerical estimate of
at least 7 on a 10-point scale) that requires rapid opioid ti-
tration to provide analgesia.3 There are no epidemiological
data to suggest how commonly pain crises occur. Our own
experience at Memorial Sloan-Kettering Cancer Center sug-
gests that of about 120 inpatient consultations a month, our
Pain and Palliative Care Service is called for what is iden-
tified as a pain crisis by the referring physician as fre-
quently as 20 to 30 times a month—the message usually con-
©2008 American Medical Association. All rights reserved.
 PERSPECTIVES ON CARE AT THE CLOSE OF LIFE
struction, his ascites, his multiple draining infected osto-
mies, and the high likelihood of perineural tumor infiltra-
tion. These pain mechanisms can be inferred from animal
and human studies of malignant bowel obstruction and tu-
mor infiltration of the viscera.17,18
Diagnostic Studies and Treatment Strategy
Mr X presented as a medical emergency with severe intol-
erable pain as his major symptom. Rapid assessment of his
medical status was necessary to establish a correct diagno-
sis and develop a treatment plan. Although this patient re-
fused further diagnostic studies, a flat plate of the abdo-
men to assess for free air and bowel dilatation or a computed
tomography scan to confirm bowel perforation to assess the
severity of bowel obstruction may be appropriate diagnos-
tic studies in this situation.19 Broad-spectrum antibiotics were
a reasonable treatment option for one aspect of his pain ex-
acerbation. The extent of the diagnostic workup to be done
depends on the clinical situation (reversible crisis vs antici-
pated worsening of a progressive disease that led to the cri-
sis), the goals of care, the patient’s wishes, and the risk-
benefit burden ratio of any diagnostic test considered. Clear
Figure. Memorial Pain Assessment Card
Memorial Pain Assessment Card
4 Mood Scale
Worst Best
mood mood
Put a mark on the line to show your mood.
1 Pain Scale
Least Worst
possible possible
pain pain
Put a mark on the line to show how much pain there is.
Each numbered item is on a card and each card is presented to the patient separately in the numbered order: (1) visual analog scale for pain intensity, (2) modified
Tursky Pain descriptors scale, (3) visual analog scale for pain relief, and (4) visual analog scale for mood.
1460 JAMA, March 26, 2008—Vol 299, No. 12 (Reprinted with Corrections)
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documentation should specify the plan and rationale for the
workup, congruent with the goals of care and options con-
sidered. This is particularly important if a decision regard-
ing further workup and or management is focused on pro-
viding the patient with comfort.7 In a patient close to death,
no further diagnostic studies should be ordered and “rou-
tine” orders should be rewritten to focus on patient comfort.
Congruent to the goals of care, rapid titration of the an-
algesias with close monitoring of the patient for pain and
adverse effects is paramount. The main principles of opi-
oid selection are outlined in BOX 2. Opioids should be ti-
trated aggressively (BOX 3, TABLE 1, and TABLE 2). Nono-
pioids such as IV ketorolac or corticosteroids to address the
inflammatory components of pain may be combined with
opioids (TABLE 3).34-36 Spinal analgesia may be advanta-
geous because of the lower opioid dose needed, along with
the possibility of using a local anesthetic.
In Mr X’s case, the medical team in consultation with an-
esthesia and palliative care services developed a treatment
strategy that reflected an end-of-life care pathway address-
ing the patient’s physical, psychological, social, and spiri-
tual needs with the needs of his family.37,38
2 Pain Description Scale
Moderate Just noticeable
Strong No pain
Mild
Excruciating Severe
Weak
Circle the word that describes your pain.
3 Relief Scale
No relief Complete
of pain relief of pain
Put a mark on the line to show how much relief you get.
©2008 American Medical Association. All rights reserved.
 PERSPECTIVES ON CARE AT THE CLOSE OF LIFE
struction, his ascites, his multiple draining infected osto-
mies, and the high likelihood of perineural tumor infiltra-
tion. These pain mechanisms can be inferred from animal
and human studies of malignant bowel obstruction and tu-
mor infiltration of the viscera.17,18
Diagnostic Studies and Treatment Strategy
Mr X presented as a medical emergency with severe intol-
erable pain as his major symptom. Rapid assessment of his
medical status was necessary to establish a correct diagno-
sis and develop a treatment plan. Although this patient re-
fused further diagnostic studies, a flat plate of the abdo-
men to assess for free air and bowel dilatation or a computed
tomography scan to confirm bowel perforation to assess the
severity of bowel obstruction may be appropriate diagnos-
tic studies in this situation.19 Broad-spectrum antibiotics were
a reasonable treatment option for one aspect of his pain ex-
acerbation. The extent of the diagnostic workup to be done
depends on the clinical situation (reversible crisis vs antici-
pated worsening of a progressive disease that led to the cri-
sis), the goals of care, the patient’s wishes, and the risk-
benefit burden ratio of any diagnostic test considered. Clear
Figure. Memorial Pain Assessment Card
Memorial Pain Assessment Card
4 Mood Scale
Worst Best
mood mood
Put a mark on the line to show your mood.
1 Pain Scale
Least Worst
possible possible
pain pain
Put a mark on the line to show how much pain there is.
Each numbered item is on a card and each card is presented to the patient separately in the numbered order: (1) visual analog scale for pain intensity, (2) modified
Tursky Pain descriptors scale, (3) visual analog scale for pain relief, and (4) visual analog scale for mood.
1460 JAMA, March 26, 2008—Vol 299, No. 12 (Reprinted with Corrections)
Downloaded From: http://jama.jamanetwork.com/ by a National University of Singapore User on 02/25/2015
documentation should specify the plan and rationale for the
workup, congruent with the goals of care and options con-
sidered. This is particularly important if a decision regard-
ing further workup and or management is focused on pro-
viding the patient with comfort.7 In a patient close to death,
no further diagnostic studies should be ordered and “rou-
tine” orders should be rewritten to focus on patient comfort.
Congruent to the goals of care, rapid titration of the an-
algesias with close monitoring of the patient for pain and
adverse effects is paramount. The main principles of opi-
oid selection are outlined in BOX 2. Opioids should be ti-
trated aggressively (BOX 3, TABLE 1, and TABLE 2). Nono-
pioids such as IV ketorolac or corticosteroids to address the
inflammatory components of pain may be combined with
opioids (TABLE 3).34-36 Spinal analgesia may be advanta-
geous because of the lower opioid dose needed, along with
the possibility of using a local anesthetic.
In Mr X’s case, the medical team in consultation with an-
esthesia and palliative care services developed a treatment
strategy that reflected an end-of-life care pathway address-
ing the patient’s physical, psychological, social, and spiri-
tual needs with the needs of his family.37,38
2 Pain Description Scale
Moderate Just noticeable
Strong No pain
Mild
Excruciating Severe
Weak
Circle the word that describes your pain.
3 Relief Scale
No relief Complete
of pain relief of pain
Put a mark on the line to show how much relief you get.
©2008 American Medical Association. All rights reserved.

alternate opioid is necessary, frequent monitoring of the pa-
tient for pain escalation, withdrawal symptoms, or overse-
dation is essential. A step-wise approach is recommended,
decreasing the methadone dose by one-third daily while add-
ing the new opioid in equianalgesic doses. This approach
helps to prevent symptoms of withdrawal from methadone
as well as adverse effects from rapid up-titration of the al-
ternate opioid. Mr X received almost 5 g of hydromor-
phone without evidence of analgesia or adverse effects, so
it could have been further escalated. Practically speaking,
using 80-mg boluses of a drug that comes in 2-mg and 10-mg
vials is onerous for pharmacists to prepare, and often there
are limited supplies available.
How difficult is it to rotate to methadone?
Any rotation to methadone requires frequent monitoring
of the patient for undertreatment, withdrawal symptoms, or
oversedation. Methadone is a unique opioid and an increas-
ing number of case reports describe improved pain relief af-
ter rotation to methadone.25-28,82,83 Patients rotated to paren-
teral methadone may have incomplete cross-tolerance. The
ratio for calculating the safe initial continuous infusion metha-
done dose can be much lower than the published single-dose
equianalgesic dose ratios (Table 2).25,26,84,85
Methadone, therefore, should be used with caution, and
consultation with a palliative care or pain consultation team
is recommended.
Pain Crisis Management and Institutional Resources
DR P: One of the pearls of wisdom that we talked about as a
team the next day is that in situations at the end of life, it’s really
important to get people involved just as if someone was having
a heart attack. In that case, you would call a cardiologist. If
someone had a dropped lung, you would call a surgeon. In a
similar way, you have to treat someone who is terminal, mean-
ing death being imminent, as almost a code, in the sense that
you have to get the people involved who can best provide care
at that point.
Mr X presented a particular challenge because the dose
of parenteral opioids that he was receiving was clearly beyond
the house officer’s experience and the house officer needed
expert consultation. This case illustrates the critical need
for a clinical pathway for an acute pain crisis and other symp-
tom management in a dying patient.86,87 Such institutional
guidelines are important for resource allocation both of staff
time and ICU bed allocation, enabling continuous moni-
toring of the high-dose opioid and ketamine infusions. Such
guidelines for management of an acute pain crisis frame a
standard of care, informing both the patient and the health
care professionals of a recommended approach, and help to
distinguish the appropriate use of rapidly escalating high-
dose opioids and other agents in a dying patient from inap-
propriate strategies of euthanasia and physician-assisted sui-
cide (illegal in all states except Oregon).88-90 The Supreme
Court decision on physician-assisted suicide endorses aggres-
sive palliative care, even to the point of sedation, in the immi-
©2008 American Medical Association. All rights reserved.
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PERSPECTIVES ON CARE AT THE CLOSE OF LIFE
nently dying and distinguishes it from physician-assisted
suicide.88,91-93
The house officer’s intent in rapidly titrating Mr X’s opioid
dose was to reduce his pain and to improve his quality of life,
albeit recognizing that this approach could potentially has-
ten the patient’s death.94 Yet 2 studies involving terminally ill
cancer patients receiving palliative care found no difference
in the time to death when comparing patients sedated to con-
trol refractory symptoms with patients who were not se-
dated.86,91 A study of survival following withdrawal of life-
sustaining measures in ICU patients who were dying observed
that the patients receiving morphine lived longer than those
who did not.92 Data from the National Hospice Outcomes
Project found opioid dosing to be associated with the time of
death but it was only a minor factor in the variation in sur-
vival.93 Despite these data, health care professionals com-
monly have concerns about their role in hastening a patient’s
death.94,95 These concerns can be addressed by institutions in
the form of guidelines or pathways that make transparent the
indications for opioid titration and symptom outcome end
points (eg, evidence of patient comfort) that allow for clear
documentation of goals of treatment.
CONCLUSION
DR P: The day after he [Mr X] passed away, the resident, the
medical student, the interns, and I got together, and we spent
almost an hour debriefing about the experience. It was an ex-
perience that I hope was as helpful for them as it was for me.
We talked about the medical aspects and what we learned. We
talked about pain management and what we learned from our
consulting services. We really spent a lot of time just talking
about death and dying, communication at that stage, and what
it was like to go home after an experience like that and to talk
to our significant others.
The palliative care consultation team became actively in-
volved with the patient when his goals of care changed to com-
fort care and when he was identified as dying. The stand-
point that a palliative care team should only become “really
involved” if the patients has a “no code” status is contrary to
the current concept of palliative care for which the goal is to
move palliative care upstream as part of comprehensive care.
Although discussion of the management of this case has been
focused on the medical management of the pain crisis, ho-
listic care of the patient and the family needs the expertise of
the other team members providing psychological support and
behavioral approaches as well as spiritual care.2,96-98 Most of
palliative care in oncology is provided by oncological teams.
Routine comprehensive symptom assessment and manage-
ment may help identify the areas for which palliative care spe-
cialists may provide direct care to the patient; support the pri-
mary service; or facilitate communications between the patient,
caregivers, and medical team.96,98-101 Institutional guidelines
can provide structure for routine palliative care assessment
to identify and address unmet palliative care needs and to tran-
sition patients to hospice care.
(Reprinted with Corrections) JAMA, March 26, 2008—Vol 299, No. 12 1465
 PERSPECTIVES ON CARE AT THE CLOSE OF LIFE

Box 3. Managing a Pain Crisis With Parenteral Opioids in Patients Currently Receiving Opioid Therapy
Group 1. Patients Who Have Inadequate Pain Relief and No Significant Opioid Adverse Effects
Continue the current opioid and use rescue doses for titration.
If taking an oral opioid, convert the patient’s rescue dose to an intravenous equivalent using relative potency tables (Table 1 and
Table 2).
Administer double the rescue dose intravenously.
Repeat same dose in 15 minutes if there is no or minimal pain relief.
If pain persists at 7 or higher on a 10-point scale without adverse effects, increase the intravenous rescue dose by 50%.
Continue to administer this dose every 15 minutes until patient experiences more than 50% pain relief or adverse effects develop.
Consider intravenous adjuvants or coanalgesics (eg, a nonsteroidal anti-inflammatory drug or corticosteroids).
Once the patient has obtained adequate pain relief, calculate the new 24-hour opioid requirements including rescue doses and
order accordingly.
Decide route of opioid administration (eg, oral, intravenous, transdermal) best suited to the patient’s ongoing analgesic needs
and adjust dose accordingly.
Group 2. Patients Who Have Significant Opioid Adverse Effects
Discontinue the current opioid and rotate the patient to a different opioid (opioid rotation).
Refer to the equianalgesic tables (Table 1 and Table 2).
If the pain control is good but significant adverse effects are present, reduce the equianalgesic dose (Table 3) of the new opioid
by 25% to 50% (accommodates for cross-tolerance); continue to monitor the patient for reduction in adverse effects and ad-
equacy of pain relief; and provide for rescue doses for breakthrough pain.
If pain control is poor and significant adverse effects are present, rotate opioids without reduction in the equianalgesic dose;
continue to monitor the patient for reduction in adverse effects and adequacy of pain relief; and provide for rescue doses.
For opioid-tolerant patients, estimate the safe starting dose of the new opioid depending on the patient’s tolerance (the higher
the previous opioid dose, the greater the level of tolerance; Table 2).
In all situations of opioid rotation, monitor the patient closely for adequacy of pain relief and reduction of adverse effects.

nomena of incomplete cross-tolerance, as evidenced by im- Use of Adjuvant Coanalgesic Medications

proved pain relief or a reduction in adverse effects follow-
ing opioid rotation, is thought to be related, in part, to a range
of interindividual pharmacogenetic factors including ge-
netic polymorphisms in the morphine gene and in drug
metabolism.52-54
When rotating from a short half-life opioid such as hy-
dromorphone or fentanyl to another opioid, calculate the
equianalgesic dose and estimate the safe starting dose (Table 1
and Table 2).20-25,27,55 In patients who have adequate anal-
gesia on their current opioid dose but intolerable or un-
manageable adverse effects, reduce the calculated equian-
algesic dose by 25% to 50% or up to 90% in case of methadone
(Box 3 and Table 2).
Opioid Adverse Effects. Nausea and vomiting, seda-
tion, delirium, respiratory depression, constipation, multi-
focal myoclonus, and seizures are known adverse effects of
opioid drugs (TABLE 4).1,56,63,68 Tolerance develops to some
of these adverse effects, although at varying rates. For ex-
ample, tolerance may develop to nausea and vomiting, res-
piratory depression, and sedation but does not develop to
constipation. Each adverse effect requires a careful assess-
ment and treatment strategy.57-62,64-68
1462 JAMA, March 26, 2008—Vol 299, No. 12 (Reprinted with Corrections)
Adjuvant coanalgesic medications should be considered early
in pain crisis management (Table 3).69 The term adjuvant
is used to describe different drugs and classes of drugs that
may enhance the effects of opioids or nonsteroidal
anti-inflammatory drugs.29 Adjuvants exert independent an-
algesic activity in certain circumstances or counteract the
adverse effects of analgesics.3,5 Introducing adjuvant coan-
algesic agents concurrently with opioid titration is recom-
mended based on the inferred mechanism of the pain crisis
and their known effectiveness in these situations. Table 3
lists some of the adjuvant coanalgesic medications that can
be administered through an IV when managing a pain
crisis.29-34,70
For Mr X, the anesthesia pain service recommended ket-
amine based on its reported efficacy in neuropathic and can-
cer pain.30,31 Ketamine, an NMDA antagonist and an anes-
thetic that does not interfere with respiratory drive, has been
shown to be a potent analgesic in low doses.71 Multiple case
series and small prospective studies using a double-blind,
placebo-controlled approach suggest that very low-dose ket-
amine may potentiate opioid analgesia and reduce pain.30-32,34
The use of ketamine may not only provide greatly im-
©2008 American Medical Association. All rights reserved.

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 PERSPECTIVES ON CARE AT THE CLOSE OF LIFE

proved pain relief but also allow for significant decreases

Table 1. Relative Single-Dose Potencies of Commonly Used Opioid
in the dose of current analgesics and sedatives. Some re- Drugs for Pain and Their Oral-Intravenous Ratios a
ports suggest that it is useful in visceral pain as well as neu- Equianalgesic
ropathic pain. Intravenous or Oral-Intravenous
Ketamine should be started at a low dose of 0.02 to 0.05 Drug Intramuscular Dose, mg Ratios
mg/kg per hour by continuous IV infusion and rapidly ti- Morphine4,20 10 3
Oxycodone4,20,21 Not available Not available
trated upward as needed, escalating the dose by up to 100%
Oxymorphone4 1 10
every 4 to 6 hours, depending on the pain intensity and ad-
Hydromorphone4,22 1.5 5
verse effect profile. In our experience, this dosing regimen
Methadone4, b 10 1-2
is both safe and well-tolerated. Cognitive adverse effects have
Levorphanol4 2 2
occurred infrequently at these doses. Because of the sever-
Fentanyl4,23,24 250 µg 1 (transdermal-
ity of his pain, Mr X eventually received 7 mg/h of IV ket- intravenous)
amine, and because he was in a closely monitored setting, a This table should be used as a guide only and not replace a more in-depth review.4
his dose could have been titrated upward even further in Individual dosing and drug selection depend on each patient’s particular situation and
comprehensive assessment.
an attempt to increase his pain relief, had he desired, to al- b Refer to Table 2 for rotation to methadone for long-term administration.

low for a decrease in his methadone requirements. How-

ever, at doses of 10 to 20 mg/h, 30% to 50% of patients are
reported to develop drowsiness, nightmares, and halluci- Table 2. Variability in Dose Ratios When Switching Oral Morphine,
Oral Hydromorphone, and Transdermal Fentanyl to Methadone a
nations.72 Due to few published data, a Cochrane review con-
Dose Morphine→Methadone Ratio25
cluded that the role of ketamine is not yet established.33 To
Morphine, mg/24 h
develop evidence-based guidelines for cancer patients, ad- 30-90 4:1
ditional studies are needed. 91-300 9:1
ⱖ300 12:1
Use of Methadone in Pain Crisis Management Hydromorphone, mg/24 h Hydromorphone→methadone ratio26
Dr S: I told him that if he wanted us to get the pain under con- ⱖ330 1.6:1
trol and if the only way that we could do this was with IV metha- ⬍330 0.95:1
done, then we thought that it did not make sense to follow his Fentanyl Fentanyl→methadone ratio27,28
QT interval, or get EKGs, and we should just put that aside. 50-2500 µg/h 250 µg/h:1 mg/h
He said he completely agreed, and his wife said she also a To change from oral morphine to oral methadone for a patient taking 80 mg/d of
morphine orally, the equivalent methadone dose based on this study (4:1 ratio) will
agreed . . . be 20 mg of methadone orally every 24 hours. For a patient taking 800 mg/d oral
Prior to this admission, methadone was the only opioid that morphine based on a 12:1 conversion ratio, the equivalent methadone dose will be
67 mg/24 h. When changing from transdermal fentanyl to oral methadone the dose
was effective in at least partially controlling Mr X’s pain. He ratio is reported to remain the same, independent of the fentanyl dose.

Table 3. Adjuvant Drugs for Parenteral Use in Pain Crisis Management a

Category/Drug Dosage Indication Comments
NSAID
Ketorolac Administer 30-60 mg initially, then Neuropathic pain Equianalgesic to morphine (10 mg IV morphine = 10 mg
15-30 mg every 6-h boluses Visceral pain IV ketorolac)
as needed for up to 5 d Bone pain Substantial GI and renal toxic effects may precipitate
Inflammatory pain renal failure in dehydrated patients
Pain crisis
Corticosteroids29
Dexamethasone High-dose regimen: 100 mg IV once, Spinal/nerve compression Potential for GI bleed, hyperglycemia, psychosis
followed by 24 mg 4 times a day Neuropathic pain
Low-dose regimen: 10 mg IV 4 times Bony metastasis
a day or 2-4 mg every 6 h, then taper
Benzodiazepines
Lorazepam 0.5-1 mg IV Anxiety Inform patient/caregiver that sedation is common
Nontolerant patient If sedation is the goal, it can be given as IV infusion
but may cause agitation in elderly or delirious patients
Midazolam 0.5-1 mg IV Anxiety Administer slowly over 2-3 min; monitor for sedation
Sedation and respiratory depression
If sedation is the goal, it can be given as an IV infusion
Tachyphylaxis is common
Anesthetic
Ketamine30-33 0.02-0.05 mg/kg per h Intractable pain Opioid-sparing dissociative agent in higher doses
Titrate up every 4-6 h as needed Neuropathic pain
Abbreviations: GI, gastrointestinal; IV, intravenous; NSAID, nonsteroidal anti-inflammatory drug.
a Indications are based on clinical experience and are not necessarily supported by trial data or US Food and Drug Administration approval.

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 PERSPECTIVES ON CARE AT THE CLOSE OF LIFE

had received 800 mg of parenteral methadone in the 24-hour
period prior to his admission to the hospital in a pain crisis.
Based on published pain practice guidelines,3,4 a bolus dose
of 80 to 160 mg (10% to 20% of the 24-hour dose) of metha-
done should be repeated every 15 minutes until the patient
experiences pain relief or dose-limiting toxicity. Because of
the prolonged QTc interval, Mr X was rotated to parenteral
hydromorphone and obtained no relief despite using 80 mg
of hydromorphone per IV with boluses of 80 mg every 10 min-
utes. After reestablishing the goals of care and declining life-
prolonging therapy, methadone was restarted and titrated up
to analgesia over the next few hours.
This clinical predicament raises several questions:
What is the relationship between parenteral methadone and
QTc prolongation?
The relationship between methadone and QTc prolonga-
tion is well described.73-79 Drug-induced long QT syndrome
is characterized by a prolonged corrected QT interval (QTc)
and increased risk of a polymorphic ventricular tachycardia,
also known as torsades de pointes. Published studies sug-
gest that QT prolongation is context-dependent and occurs
more frequently with high doses of methadone, concomi-
tant administration of CYP3A4 inhibitors such as erythro-
mycin, dicumarol, and other drugs (which can inhibit the bio-
transformation of methadone), hypokalemia, hepatic failure,
and administration of other QT-prolonging agents such as
chlorobutanol, the preservative in parenteral methadone prepa-
rations.80 Clearly, the benefit of methadone in the individual
patient needs to be weighed against the potential for risk of
arrhythmia. Each of the associated factors that could con-
tribute to methadone toxicity need to be evaluated in pa-
tients with a history of significant QTc prolongation.
In Mr X, electrolyte correction and the use of preservative-
free methadone would have been one approach to consider
to reduce risk and to allow continuation of methadone.75
Despite the potential risk and consequences of torsades de
pointes, his goals of care and lack of pain control with other
agents favored continuation of parenteral methadone.
Could the hydromorphone have been titrated up further?
Abrupt discontinuation of methadone has been reported
to cause pain escalation in 12 of 13 patients who were re-
ceiving methadone as a third- or fourth-line opioid, de-
spite titration of the alternative opioid to the highest toler-
ated dose.81 If rotation from high-dose methadone to an

Table 4. Opioid-Related Adverse Effects During Rapid Opioid Escalation Management Influenced by Goals of Care1,27,28,51
More Likely to Be Seen in Patients
Adverse Effects With the Following Conditions Treatment
Myoclonus Renal insufficiency Use benzodiazepines56
Hepatic insufficiency Correct electrolytes
Rotate opioid
Seizures Progressive myoclonus Use benzodiazepines
Reduce opioid
Rotate opioid57,58
Delirium (both hypoactive Renal insufficiency Discontinue drugs contributing to effect
and hyperactive) Hepatic insufficiency Avoid sedating medications, unless essential
Advanced age Use antipsychotic medications59,60
Alcohol withdrawal Decrease opioid dose
Benzodiazepine withdrawal Rotate to opioid with short half-life and no active metabolites
Dementia (eg, fentanyl)
Brain metastasis
Sedation Renal insufficiency Discontinue all medications that can contribute to the sedation
Hepatic insufficiency Decrease opioid dose
Advanced age Rotate to opioid with short half-life and no active metabolite
Dementia (eg, fentanyl)
Brain metastasis Use psychostimulant55,61,62
Respiratory depression COPD Reduce opioid dose
Restrictive lung disease (following Rotate opioid to short half-life drug without active metabolites
lobectomy, postradiation fibrosis) Use diluted naloxone63, a
Upper airway compromise If no response to naloxone, consider intubation
Bacterial and viral pneumonia
Pruritus Morphine Rotate opioid to another opioid with less histamine release potential64,65
Urinary retention Spinal cord disease Opioid dose reduction66
Prostate enlargement Opioid rotation
Nausea Previous history of nausea Antinausea medications67
Opioid rotation
Abbreviation: COPD, chronic obstructive pulmonary disease.
a Naloxone has the potential to increase pain in nearly all cases and should be administered with caution, understanding that only unacceptable and life-threatening opioid-induced
sedation and respiratory depression should be reversed by naloxone (respirations ⬍8/min, shallow respirations, O2 saturation less than 92%, difficult to arouse). If a decision to
use naloxone is made, 1 ampule (0.4 mg) needs to be diluted in 9 mL of normal saline and administered slowly, 0.1 to 0.2 mg (1- to 2-mL increments) every 2 to 3 minutes to
achieve the desirable level of opioid-agonist respiratory depression reversal and alertness without pain flare. The half-life of naloxone is shorter than for many oral, long-acting
opioids, so repeated doses of naloxone may be needed, and careful patient monitoring with continuous pulse oximetry and nasal cannula oxygen are recommended. If the
respiratory depressant effects of a long half-life drug such as methadone is required, a naloxone infusion should be used (2 mg/50 mL of dextrose with water or normal saline [0.4
mg]. Infuse 0.4 to 0.8 mg/h. Titrate infusion rate to desired effect). For opioid-induced respiratory depression and sedation caused by partial agonists/antagonists, much larger
doses of naloxone may be required. For patients taking buprenorphine, naloxone may be ineffective. If intravenous boluses (typically 0.4-2 mg) are effective, start naloxone drip
if on fentanyl patch, methadone, or other long-acting medications/delivery systems. Monitor for pain escalation after administering naloxone.

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alternate opioid is necessary, frequent monitoring of the pa-
tient for pain escalation, withdrawal symptoms, or overse-
dation is essential. A step-wise approach is recommended,
decreasing the methadone dose by one-third daily while add-
ing the new opioid in equianalgesic doses. This approach
helps to prevent symptoms of withdrawal from methadone
as well as adverse effects from rapid up-titration of the al-
ternate opioid. Mr X received almost 5 g of hydromor-
phone without evidence of analgesia or adverse effects, so
it could have been further escalated. Practically speaking,
using 80-mg boluses of a drug that comes in 2-mg and 10-mg
vials is onerous for pharmacists to prepare, and often there
are limited supplies available.
How difficult is it to rotate to methadone?
Any rotation to methadone requires frequent monitoring
of the patient for undertreatment, withdrawal symptoms, or
oversedation. Methadone is a unique opioid and an increas-
ing number of case reports describe improved pain relief af-
ter rotation to methadone.25-28,82,83 Patients rotated to paren-
teral methadone may have incomplete cross-tolerance. The
ratio for calculating the safe initial continuous infusion metha-
done dose can be much lower than the published single-dose
equianalgesic dose ratios (Table 2).25,26,84,85
Methadone, therefore, should be used with caution, and
consultation with a palliative care or pain consultation team
is recommended.
Pain Crisis Management and Institutional Resources
DR P: One of the pearls of wisdom that we talked about as a
team the next day is that in situations at the end of life, it’s really
important to get people involved just as if someone was having
a heart attack. In that case, you would call a cardiologist. If
someone had a dropped lung, you would call a surgeon. In a
similar way, you have to treat someone who is terminal, mean-
ing death being imminent, as almost a code, in the sense that
you have to get the people involved who can best provide care
at that point.
Mr X presented a particular challenge because the dose
of parenteral opioids that he was receiving was clearly beyond
the house officer’s experience and the house officer needed
expert consultation. This case illustrates the critical need
for a clinical pathway for an acute pain crisis and other symp-
tom management in a dying patient.86,87 Such institutional
guidelines are important for resource allocation both of staff
time and ICU bed allocation, enabling continuous moni-
toring of the high-dose opioid and ketamine infusions. Such
guidelines for management of an acute pain crisis frame a
standard of care, informing both the patient and the health
care professionals of a recommended approach, and help to
distinguish the appropriate use of rapidly escalating high-
dose opioids and other agents in a dying patient from inap-
propriate strategies of euthanasia and physician-assisted sui-
cide (illegal in all states except Oregon).88-90 The Supreme
Court decision on physician-assisted suicide endorses aggres-
sive palliative care, even to the point of sedation, in the immi-
©2008 American Medical Association. All rights reserved.
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PERSPECTIVES ON CARE AT THE CLOSE OF LIFE
nently dying and distinguishes it from physician-assisted
suicide.88,91-93
The house officer’s intent in rapidly titrating Mr X’s opioid
dose was to reduce his pain and to improve his quality of life,
albeit recognizing that this approach could potentially has-
ten the patient’s death.94 Yet 2 studies involving terminally ill
cancer patients receiving palliative care found no difference
in the time to death when comparing patients sedated to con-
trol refractory symptoms with patients who were not se-
dated.86,91 A study of survival following withdrawal of life-
sustaining measures in ICU patients who were dying observed
that the patients receiving morphine lived longer than those
who did not.92 Data from the National Hospice Outcomes
Project found opioid dosing to be associated with the time of
death but it was only a minor factor in the variation in sur-
vival.93 Despite these data, health care professionals com-
monly have concerns about their role in hastening a patient’s
death.94,95 These concerns can be addressed by institutions in
the form of guidelines or pathways that make transparent the
indications for opioid titration and symptom outcome end
points (eg, evidence of patient comfort) that allow for clear
documentation of goals of treatment.
CONCLUSION
DR P: The day after he [Mr X] passed away, the resident, the
medical student, the interns, and I got together, and we spent
almost an hour debriefing about the experience. It was an ex-
perience that I hope was as helpful for them as it was for me.
We talked about the medical aspects and what we learned. We
talked about pain management and what we learned from our
consulting services. We really spent a lot of time just talking
about death and dying, communication at that stage, and what
it was like to go home after an experience like that and to talk
to our significant others.
The palliative care consultation team became actively in-
volved with the patient when his goals of care changed to com-
fort care and when he was identified as dying. The stand-
point that a palliative care team should only become “really
involved” if the patients has a “no code” status is contrary to
the current concept of palliative care for which the goal is to
move palliative care upstream as part of comprehensive care.
Although discussion of the management of this case has been
focused on the medical management of the pain crisis, ho-
listic care of the patient and the family needs the expertise of
the other team members providing psychological support and
behavioral approaches as well as spiritual care.2,96-98 Most of
palliative care in oncology is provided by oncological teams.
Routine comprehensive symptom assessment and manage-
ment may help identify the areas for which palliative care spe-
cialists may provide direct care to the patient; support the pri-
mary service; or facilitate communications between the patient,
caregivers, and medical team.96,98-101 Institutional guidelines
can provide structure for routine palliative care assessment
to identify and address unmet palliative care needs and to tran-
sition patients to hospice care.
(Reprinted with Corrections) JAMA, March 26, 2008—Vol 299, No. 12 1465
 PERSPECTIVES ON CARE AT THE CLOSE OF LIFE
Financial Disclosures: None reported.
Funding/Support: The Perspectives on Care at the Close of Life section is made
possible by a grant from the California HealthCare Foundation.
Role of the Sponsors: The funding source had no role in the preparation, review,
or approval of the manuscript.
Other Resources: For a list of related references, see the JAMA Web site at http:
//www.jama.com.
REFERENCES
1. Moryl N, Carver A, Foley KM. Pain and palliation. In: Holland JF, Frei E, eds.
Cancer Medicine. 7th ed. Hamilton, ON: BC Decker Inc; 2006:1113-1124.
2. Meyers FJ, Linder J, Beckett L, Christensen S, Blais J, Gandara DR. Simulta-
neous care: a model approach to the perceived conflict between investigational
therapy and palliative care. J Pain Symptom Manage. 2004;28(6):548-556.
3. NCCN Clinical Practice Guidelines in Oncology: Adult Cancer Pain; 2007. http:
//www.nccn.org/professionals/physician_gls/PDF/pain.pdf. Accessed February 27,
2008.
4. American Pain Society. Principles of Analgesic Use in the Treatment of Acute
Pain and Cancer Pain. 5th ed. Glenview, IL: American Pain Society; 2007.
5. NCCN Clinical Practice Guidelines: Palliative Care; 2007. http://www.nccn.org
/professionals/physician_gls/PDF/palliative.pdf. Accessed February 27, 2008.
6. Foley KM. Management of cancer pain. In: DeVita VT, Hellman S, Rosenberg
SA, eds. Cancer Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lip-
pincott Williams & Wilkins; 2005:2615-2649.
7. Steinhauser KE, Christakis NA, Clipp EC, et al. Factors considered important at
the end-of-life by patients, family, physicians and other care providers. JAMA. 2000;
284(19):2476-2482.
8. Coyle N. The hard work of living in the face of death. J Pain Symptom Manage.
2006;32(3):266-274.
9. Cherny NI, Foley KM. Suffering in the advanced cancer patient: a definition
and taxonomy. J Palliat Care. 1994;10(2):57-70.
10. Wilson KG, Chochinov HM, Skirko M, et al. Depression and anxiety disorders
in palliative cancer care. J Pain Symptom Manage. 2007;33(2):118-129.
11. Daut RL, Cleeland CS, Flanery R. Development of the Wisconsin Brief Pain
Inventory to assess pain in cancer and other diseases. Pain. 1983;17(2):197-
210.
12. Melzak R. The McGill Pain Questionnaire. In: Melzak R, ed. Pain Measure-
ment and Assessment. New York, NY: Raven Press; 1993.
13. Bijur PE, Silver W, Gallagher J. Reliability of the Visual Analog Scale for Mea-
surement of Acute Pain. Acad Emerg Med. 2001;8(12):1153-1157.
14. Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment Sys-
tem (ESAS): a simple method for the assessment of palliative care patients. J Pal-
liat Care. 1991;7(2):6-9.
15. Portenoy RK, Thaler HT, Kornblith AB, et al. The Memorial Symptom Assess-
ment Scale: an instrument for the evaluation of symptom prevalence, character-
istics and distress. Eur J Cancer. 1994;30A(9):1326-1336.
16. Fishman B, Pasternak S, Wallenstein SL, Houde RW, Holland JC, Foley KM.
The Memorial Pain Assessment Card. A valid instrument for the evaluation of can-
cer pain. Cancer. 1987;60(5):1151-1158.
17. Sandner-Kiesling A, Bantel C. New models for visceral pain. Curr Opin
Anaesthesiol. 2003;16(5):535-540.
18. Anthony T, Baron T, Mercandante S, et al. Report of the clinical protocol com-
mittee: development of randomized trials for malignant bowel obstruction. J Pain
Symptom Manage. 2007;34(1 suppl):S49-S59.
19. Ripamonti C, Twycross R, Baines M, et al; Working Group of the European
Association for Palliative Care. Clinical practice recommendations for the man-
agement of bowel obstruction in patients with end-stage cancer. Support Care
Cancer. 2001;9(4):223-233.
20. Colucci RD, Swanton RE, Thomas GB, Kaiko RF. Relative variability in bio-
availability of oral controlled-release formulations of oxycodone and morphine.
Am J Ther. 2001;8(4):231-236.
21. Ordóñez A, González BM, Espinosa AE. Oxycodone: a pharmacological and
clinical review. Clin Transl Oncol. 2007;9(5):298-307.
22. Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical
applications in cancer patients. Support Care Cancer. 2001;9(2):84-96.
23. Muijsers RB, Richard BR, et al. Transdermal fentanyl: an updated review of
its pharmacological properties and therapeutic efficacy in chronic cancer pain control.
Drugs. 2001;61(15):2289-2307.
24. Sopalski MA. Pain control with fentanyl patch. J Hospice Pall Nursing. 2007;
9(1):13-14.
25. Bruera E, Pereira J, Wantanabe S, Belzile M, Kuehn N, Hanson J. Opioid ro-
tation in patients with cancer pain: a retrospective comparison of dose ratios be-
tween methadone, hydromorphone, and morphine. Cancer. 1996;78(4):852-
871.
26. Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone
for cancer pain. Pain. 1997;70(2-3):109-115.
27. Santiago-Palma J, Khojainova N, Kornick C, et al. Intravenous methadone in
1466 JAMA, March 26, 2008—Vol 299, No. 12 (Reprinted with Corrections)
Downloaded From: http://jama.jamanetwork.com/ by a National University of Singapore User on 02/25/2015
the management of chronic cancer pain: safe and effective starting doses when
substituting methadone for fentanyl. Cancer. 2001;92(7):1919-1925.
28. Mercadante S, Villari P, Ferrera P, Casuccio A, Gambaro V. Opioid plasma
concentrations during a switch from transdermal fentanyl to methadone. J Palliat
Med. 2007;10(2):338-344.
29. Mercadante SL, Berchovich M, Casuccio A, Fulfaro F, Mangione S. A pro-
spective randomized study of corticosteroids as adjuvant drugs to opioids in ad-
vanced cancer patients. Am J Hosp Palliat Care. 2007;24(1):13-19.
30. Fine PG. Low-dose ketamine in the management of opioid nonresponsive ter-
minal cancer pain. J Pain Symptom Manage. 1999;17:296-300.
31. Ben-Ari A, Lewis MC, Davidson E. Chronic administration of ketamine for
analgesia. J Pain Palliat Care Pharmacother. 2007;21(1):7-14.
32. Mercadante S. Ketamine in cancer pain an update. Palliat Med. 1996;10
(3):225-230.
33. Bell RF, Dahl JB, Moore RA, et al. Peri-operative ketamine for acute post-
operative pain: a quantitative and qualitative systematic review (Cochrane review).
Acta Anaesthesiol Scand. 2005;49(10):1405-1428.
34. Visser E, Schug SA. The role of ketamine in pain management. Biomed
Pharmacother. 2006;60(7):341-348.
35. Gutstein BH, Akil A. Opioid analgesics. In: Hardman JG, Limbird LE, eds. Good-
man and Gillman The Pharmacological Basis of Therapeutics. 10th ed. New York,
NY: McGraw-Hill Companies Inc North America; 2001:598-599.
36. Feuer DJ, Broadley KE. Corticosteroids for the Resolution of Malignant Bowel
Obstruction in Advanced Gynecological and Gastrointestinal Cancer. Chichester,
UK: The Cochrane Library, John Wiley & Sons Ltd; 2004.
37. Bookbinder M, Blank AE, Arney E, et al. Improving end-of-life care: develop-
ment and pilot-test of a clinical pathway. J Pain Symptom Manage. 2005;29
(6):529-543.
38. Ellershaw JE, Murphy D. The Liverpool Care Pathway (LCP) influencing the
UK national agenda on care of the dying. Int J Palliat Nurs. 2005;11(3):132-
134.
39. Cherny NI. Sedation for the care of patients with advanced cancer. Nat Clin
Pract Oncol. 2006;3(9):492-500.
40. Lo B, Rubenfeld G. Palliative sedation in dying patients: “we turn to it when
everything else hasn’t worked.” JAMA. 2005;294(14):1810-1816.
41. Klepstad P, Kaasa S, Skauge M, Borchgrevink PC. Pain intensity and side ef-
fects during titration of morphine to cancer patients using a fixed schedule dose
escalation. Acta Anaesthesiol Scand. 2000;44(6):656-664.
42. Klepstad P, Kaasa S, Borchgrevink PC. Start of oral morphine to cancer pa-
tients: effective serum morphine concentrations and contribution from morphine-
6-glucuronide to the analgesia produced by morphine. Eur J Clin Pharmacol. 2000;
55(10):713-719.
43. Owen JA, Sitar DS, Berger L, Brownell L, Duke PC, Mitenko PA. Age-related
morphine kinetics. Clin Pharmacol Ther. 1983;34(3):364-368.
44. Portenoy RK, Foley KM, Stuhnan J, et al. Plasma morphine and morphine-6-
glucuronide during chronic morphine therapy for cancer pain: plasma profiles, steady-
state concentrations and the consequences of renal failure. Pain. 1991;47(1):
13-19.
45. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evi-
dence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol. 2000;
27(7):524-528.
46. Manfredi PL, Foley KM, Payne R, Houde R, Inturrisi CE. Parenteral metha-
done: an essential medication for the treatment of pain. J Pain Symptom Manage.
2003;26(2):687-688.
47. Bruera E, Sweeney C. Methadone use in cancer patients with pain: a review.
J Palliat Med. 2002;5(1):127-138.
48. Davis MP, Walsh D. Methadone for relief of cancer pain a review of phar-
macokinetics, pharmacodynamics, drug interactions and protocols of administration.
Support Care Cancer. 2001;9(2):73-83.
49. Gorman AL, Elliott KJ, Inturrisi CE. The D- and L-isomers of methadone bind
to the non-competitive site on the N-methyl D-aspartate (NMDA) receptor in rat
forebrain and spinal cord. Neurosci Lett. 1997;223(1):5-8.
50. Codd EE, Shank RP, Schupsky JJ, Raffa RB. Serotonin and norepinephrine up-
take inhibiting activity of centrally acting analgesics: structural determinants and
role in antinociception. J Pharmacol Exp Ther. 1995;274(3):1263-1270.
51. Cherny NI, Chang V, Frager G, et al. Opioid pharmacotherapy in the man-
agement of cancer pain: a survey of strategies used by pain physicians for the se-
lection of analgesic drugs and routes of administration. Cancer. 1995;76(7):1283-
1293.
52. Pasternak GW. Molecular biology of opioid analgesia. J Pain Symptom Manage.
2005;29(5 suppl):S2-S9.
53. Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin Phar-
macol Ther. 2007;81(3):429-444.
54. Tomalik-Scharte D, Lazar A, Fuhr U, Kirchheiner J. The clinical role of genetic
polymorphisms in drug-metabolizing enzymes. Pharmacogenomics. 2008;8(1):
4-15.
55. Foley KM. Changing concepts of tolerance to opioids: what the cancer pa-
tient has taught us. In: Chapman CR, Foley KM, eds. Current & Emerging Issues
©2008 American Medical Association. All rights reserved.

in Cancer Pain: Research & Practice. New York, NY: Raven Press; 1993:
331-349.
56. Wilson RK, Weissman DE. Neuroexcitatory effects of opioids: patient assess-
ment #57. J Palliat Med. 2004;7(4):579.
57. Marinella MA. Meperidine-induced generalized seizures with normal renal
function. South Med J. 1997;90(5):556-558.
58. Challoner KR, McCarron MM, Newton EJ. Pentazocine (Talwin) intoxication:
report of 57 cases. J Emerg Med. 1990;8(1):67-74.
59. Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol,
chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS
patients. Am J Psychiatry. 1996;153(2):231-237.
60. Boettger S, Breitbart W. Atypical antipsychotics in the management of de-
lirium: a review of the empirical literature. Palliat Support Care. 2005;3(3):227-
237.
61. Prommer E. Modafinil: is it ready for prime time? J Opioid Manag. 2006;
2(3):130-136.
62. Reissig JE, Rybarczyk AM. Pharmacologic treatment of opioid-induced seda-
tion in chronic pain. Ann Pharmacother. 2005;39(4):727-731.
63. Mercadante S. Pathophysiology and treatment of opioid-related myoclonus
in cancer patients. Pain. 1998;74(1):5-9.
64. Tarcatu D, Tamasdan C, Moryl N, Obbens E. Are we still scratching the sur-
face? a case of intractable pruritus following systemic opioid analgesia. J Opioid
Manag. 2007;3(3):167-170.
65. Katcher J, Walsh D. Opioid-induced itching: morphine sulfate and hydromor-
phone hydrochloride. J Pain Symptom Manage. 1999;17(1):70-72.
66. Barretto de Carvalho Fernandes MC, Vieira da Costa V, Saraiva RA. Postop-
erative urinary retention: evaluation of patients using opioids analgesic. Rev Lat
Am Enfermagem. 2007;15(2):318-322.
67. Bruera E, Belzile M, Neumann C, Harsanyi Z, Babul N, Darke A. A double-
blind, crossover study of controlled-release metoclopramide and placebo for the
chronic nausea and dyspepsia of advanced cancer. J Pain Symptom Manage. 2000;
19(6):427-435.
68. McNicol E, Horowicz-Mehler N, Fisk RA, et al; American Pain Society. Man-
agement of opioid side effects in cancer-related and chronic non-cancer pain: a
systematic review. J Pain. 2003;4(5):231-256.
69. Lussier D, Huskey AG, Portenoy RK. Adjuvant analgesics in cancer pain
management. Oncologist. 2004;9(5):571-591.
70. Wiffen P, Collins S, McQuay H, Carroll D, Jadad A, Moore A. Anticonvulsant
drugs for acute and chronic pain. Cochrane Database Syst Rev. 2000;3(3):CD001133.
71. Edwards ND, Fletcher A, Cole JR, Peacock JE. Combined infusions of mor-
phine and ketamine for postoperative pain in elderly patients. Anaesthesia. 1993;
48(2):124-127.
72. White PR, Way WL, Trevor AL. Ketamine—its pharmacology and therapeu-
tic uses. Anesthesiology. 1982;56:119-136.
73. Wedam EF, Bigelow GE, Johnson RE, et al. QT-interval effects of methadone,
levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med. 2007;
167(22):2469-2475.
74. Krantz MJ, Lowery CM, Martell BA, Gourevitch MN, Arnsten JH. Effects of
methadone on QT-interval dispersion. Pharmacotherapy. 2005;25(11):1523-
1529.
75. Sekine R, Obbens E, Coyle N, Inturrisi CE. The successful use of a parenteral
methadone in a patient with a prolonged QTc Interval. J Pain Symptom Manage.
2007;34(5):566-569.
76. Katchman AN, Koerner J, Tosaka T, Woosley RL, Ebert SN. Comparative evalu-
ation of HERG currents and QT intervals following challenge with suspected tor-
sadogenic and nontorsadogenic drugs. J Pharmacol Exp Ther. 2006;316(3):1098-
1106.
77. Kornick CA, Kilborn MJ, Santiago-Palma J, et al. QTc interval prolongation
associated with intravenous methadone. Pain. 2003;105(3):499-506.
78. Ehret GB, Desmeules JA, Broers B. Methadone-associated long QT syn-
drome: improving pharmacotherapy for dependence on illegal opioids and les-
sons learned for pharmacology. Expert Opin Drug Saf. 2007;6(3):289-303.
©2008 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a National University of Singapore User on 02/25/2015
PERSPECTIVES ON CARE AT THE CLOSE OF LIFE
79. Al-Khatib SM, LaPointe NM, Kramer JM, Califf RM. What clinicians should
know about the QT interval. JAMA. 2003;289(16):2120-2127.
80. Kornick CA, Kilborn MJ, Santiago-Palma J, et al. QTc interval prolongation
associated with intravenous methadone. Pain. 2003;105:499-506.
81. Moryl N, Santiago-Palma J, Kornick C, et al. Pitfalls of opioid rotation: sub-
stitution another opioid for methadone in patients with cancer pain. Pain. 2002;
96(3):325-328.
82. Crews JC, Sweeney NJ, Denson DD. Clinical efficacy of methadone in pa-
tients refractory to other mu-opioid receptor agonist analgesics for management
of terminal cancer pain: case presentations and discussion of incomplete cross-
tolerance among opioid agonist analgesics. Cancer. 1993;72(7):2266-2272.
83. Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev. 2004;
2(2):CD003971.
84. Kloke M, Rapp M, Bosse B, Kloke O. Toxicity and/or insufficient analgesia to
opioid therapy risk factors and the impact of changing the opioid. A retrospective
analysis of 273 patients observed at a single center. Support Care Cancer. 2000;
8(6):479-486.
85. Houde RW, Wallenstein SL, Beaver WT. Evaluation of analgesics in patients
with cancer pain. In: Lasagna L, ed. International Encyclopedia of Pharmacology
and Therapeutics. Oxford, United Kingdom: Pergamon Press; 1966:59-98.
86. Ventafridda V, Ripamonti C, DeConno F, Tanburini M, Cassileth BR. Symp-
tom prevalence and control during cancer patient’s last days of life. J Palliat Care.
1990;6(3):7-11.
87. Foley KM, Gelband H, eds. Improving Palliative Care for Cancer. Washing-
ton, DC: Institute of Medicine Report, National Academies Press; 2001.
88. Burt RA. The Supreme Court speaks: not assisted suicide but a constitutional
right to palliative care. N Engl J Med. 1997;337(17):1234-1236.
89. Sulmasy DP, Ury WA, Ahronheim JC, et al. Publication of papers on assisted
suicide and terminal sedation. Ann Intern Med. 2000;133(7):564-565.
90. Cranford RE, Gensinger R. Hospital policy on terminal sedation and euthanasia.
HEC Forum. 2002;14(3):259-264.
91. Stone P, Phillips C, Spruyt O, Waight C. A comparison of the use of sedatives
in a hospital support team and in a hospice. Palliat Med. 1997;11(2):140-144.
92. Wilson WC, Smedira NG, Fink C, McDowell JA, Luce JM. Ordering and ad-
ministration of sedatives and analgesics during the withholding and withdrawal
of life support from critically ill patients. JAMA. 1992;267(7):949-953.
93. Portenoy RK, Sibireceva U, Smout R, et al. Opioid use and survival at the end
of life: a survey of hospice population. J Pain Symptom Manage. 2006;32(6):
532-540.
94. Kaldjian LC, Wu BJ, Kirkpatrick JN, Thomas-Geevarghese A, Vaughan-
Sarrazin M. Medical house officers’ attitudes toward vigorous analgesia, terminal
sedation, and physician-assisted suicide. Am J Hosp Palliat Care. 2004;21(5):
381-387.
95. Carver AC, Vickrey BG, Bernat JL, Keran C, Ringel SP, Foley KM. End-of-life
care: a survey of US neurologists’ attitudes, behavior, and knowledge. Neurology.
1999;53(2):284-293.
96. Berzoff J, Silverman P. Living With Dying. New York, NY: Columbia Univer-
sity Press; 2004.
97. Sulmasy DP. A biopsychosocial-spiritual model for the care of patients at the
end of life. Gerontologist. 2002;42:24-33.
98. Murillo M, Holland JK. Clinical practice guidelines for the management
of psychosocial disorders at the end-of-life. Palliat Support Care. 2004;2(1):65-
77.
99. Cohen MZ, Easley MK, Ellis C, et al. JCAHO. Cancer pain management and
the JCAHO’s pain standards an institutional challenge. J Pain Symptom Manage.
2003;25(6):519-527.
100. Redinbaugh EM, Sullivan AM, Block SD, et al. Doctors’ emotional reaction
to recent death of a patient: cross sectional study of hospital doctors. BMJ. 2003;
327(7408):185.
101. Braiteh F, El Osta B, Palmer JL, Reddy SK, Bruera E. Characteristics, findings,
and outcomes of palliative care inpatient consultations at a comprehensive cancer
center. J Palliat Med. 2007;10(4):948-955.
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 WEB-ONLY CONTENT
Web Sites for End-of-Life Care Resources
NATIONAL CONSENSUS
PROJECT FOR QUALITY
PALLIATIVE CARE
http://www.nationalconsensusproject.org
Consensus guidelines published in
2004 to support the development and
delivery of palliative care.
NATIONAL COMPREHENSIVE
CANCER NETWORK
GUIDELINES
http://www.nccn.org
Evidence-based guidelines includ-
ing areas of pain, palliative care, and
other common symptoms in cancer.
AMERICAN PAIN SOCIETY
GUIDELINES FOR CANCER PAIN
http://www.ampainsoc.org
©2008 American Medical Association. All rights reserved.
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Principles of pain management with
emphasis on analgesic treatments (re-
vised in 2003).
CITY OF HOPE
PAIN & PALLIATIVE CARE
RESOURCE CENTER
http://prc.coh.org
A Web-based resource including
more than 400 materials and links
related to pain and palliative care.
EDUCATION FOR PHYSICIANS
ON END-OF-LIFE CARE
http://www.epec.net
These lectures combine didactic
sessions, videotape presentations,
interactive discussions, and practical
exercises.
(Reprinted) JAMA, March 26, 2008—Vol 299, No. 12
END OF LIFE/PALLIATIVE
RESOURCE CENTER
http://www.eperc.mcw.edu
This is a resource for end-of-life
and palliative health care profession-
als that offers tutorials, including
Fast Facts and other educational
materials.
PALLIATIVE CARE
LEADERSHIP CENTERS
http://capc.org/palliative-care-
leadership-initiative
Six institutions with exemplary
palliative care programs offer train-
ing and mentoring to help institu-
tions launch or expand a palliative
care program.
E1