1
Florida Heart CPR*
Pain Management at the End of Life
3 hours
Learning Objectives
Upon completion of this activity, participants will be able to:
1. Describe the prevalence and significance of pain at the end of life.
2. Identify techniques to assess pain in patients, including those unable to
provide verbal reports;
3. List differential features of nociceptive and neuropathic pain states;
4. Describe effective nonpharmacological means to relieve pain;
5. Recognize the therapeutic benefits and potential adverse effects
associated with opioid and nonopioid pharmacotherapy for acute and
chronic pain states at end-of-life.
Introduction
The end stages of chronic, progressive, life-limiting diseases bring a host of difficult
symptoms and causes of suffering. There are disease-mediated symptoms, such as
pain, dyspnea, fatigue, and loss of mobility, and there are the accompanying emotional
states, such as depression, anxiety, and a sense of uselessness.[1] These symptoms
and states intertwine and interact in a complex manner, and each one deserves
attention.
Of the many symptoms experienced by those at the end of life, pain is one of the most
common and most feared.[2,3] Pain is often undertreated, even when prevalence rates
and syndromes are well understood and the means of relief are within all practitioners'
capabilities to provide, directly or through consultation. With careful assessment and a
comprehensive plan of care that addresses the various aspects of the patient's needs,
pain can be controlled in the vast majority of cases. Awareness and provision of basic
and specialized interventions can ensure comfort for all patients through the final stages
of a terminal illness. This is equally important in order to prevent prolonged and
pathologic grief in surviving loved ones.
All the members of a palliative care team play important roles in comprehensive pain
management. Both physicians' and nurses' roles begin with assessment and continue
throughout the development of a plan of care and its implementation. Rehabilitation
specialists, clinical pharmacists, psychologists, social workers, and spiritual counselors
also provide important elements in helping patients optimize their quality of life, stay
comfortable, heal relationships, complete unfinished business, and find peace as they
approach death. To provide optimal pain control, all healthcare professionals must
understand the prevalence of pain at the end of life, the treatments used to provide
relief, and the barriers that prevent good management.
Florida Heart CPR*
End of life pain mgt
2
To illustrate some common scenarios, we present 3 different fictional, but typical, case
studies.
Case 1: Eleanor is a frail, 78-year-old woman who lives on her own with assistance
from a homecare nurse and from a daughter who lives nearby. She was admitted to the
hospital with acute respiratory failure due to bronchitis. She has advanced chronic
obstructive pulmonary disease (COPD), with general fatigue and a poor appetite, and
reports severe, debilitating pain in the midthoracic region from postherpetic neuralgia
(PHN). She also struggles with coronary artery disease and attendant angina pectoris
that is usually relieved with nitrates. Eleanor says that she has been feeling "pretty low"
lately and finds herself becoming irritated at small events. She characterizes her pain as
"bad as it can be" (see Figure 1). After a 2- to 3-day intensive care unit (ICU) stay, she
will soon be ready for discharge. However, her pain from PHN is still not controlled, and
her life expectancy is most likely limited due to her ongoing comorbidities. She does not
have a written advanced directive. The hospital staff discuss the next step.
Prevalence of Pain at the End of Life
Assessing pain in patients approaching the end of life requires a multifactorial
evaluation. It is important to acknowledge and address the prevalence, high incidence,
and serious adverse consequences of pain in the end-stage conditions that affect
patients with advanced medical illness, such as controlled and uncontrolled cancer;
heart disease; HIV disease; neurodegenerative diseases (eg, ALS and multiple
sclerosis); and end-stage renal and respiratory diseases (see Figures 2 and 3).[4,5]
These conditions may also be accompanied by other pain-producing disorders that may
require separate treatments, as in the case above.
The prevalence of pain in the terminally ill varies by diagnosis and demographics.
Approximately one third of the people who are actively receiving treatment for cancer
and two thirds of those with advanced malignant disease experience pain. [6-9] Almost
75% of patients with advanced cancer who are admitted to the hospital report pain upon
admission.[10] In a study of cancer patients who were very near the end of life, pain
occurred in 54% and 34% at 4 weeks and 1 week prior to death, respectively. [11] In a
recent study by Goudas and colleagues[12] that compiled the results of 28 epidemiologic
surveys, the study authors found that, in one study of over 35,000 Japanese cancer
patients, 68% to 72% of patients in the terminal stages reported pain. In another study
of over 13,000 cancer patients in US nursing homes, an average of 30% of the patients
reported daily pain. In those patients, pain varied according to age, sex, race, marital
status, physical function, depression, and cognitive status.[12]
In other studies of patients admitted to palliative care units, pain often is the dominant
symptom, along with fatigue and dyspnea.[2] Until recently, it was widely believed that
patients dying from nonmalignant disease did not have high levels of pain. However, it
is now known that patients dying from cardiac failure, COPD, end-stage renal disease,
and other end-stage diseases suffer similar levels of pain to those found in patients with
Florida Heart CPR*
End of life pain mgt
3
malignant disease.[13,14] People at particular risk for undertreatment include the elderly,
minorities, and women.[15,16]
More recently, an attempt has been made to characterize the pain experience of those
with HIV disease, a disorder frequently seen in palliative care settings. Over 56% of
patients with HIV disease report pain, with the most common symptoms being
headache, abdominal pain, chest pain, and neuropathies.[4,5,17,18] Lower CD4+ cell
counts and HIV-1 RNA levels are associated with higher rates of neuropathy.[17,18] There
have been many reports of undertreatment of patients with HIV disease, including those
patients with a history of addictive disease.[19,20]
General Principles of Assessing and Managing Pain
Assessment of pain, including a thorough history and comprehensive physical exam,
guides indications for diagnostic studies and the development of the pharmacologic and
nonpharmacologic treatment plan. The primary source of information should be a
patient's self-report. There are many different pain rating scales available, ranging from
complex multidimensional tools to very simple numeric and picture scales, which can
help patients identify pain and then document the efficacy of treatment. When using
pain scales, be sure to follow the directions for administration carefully.
A pain scale that suits a given patient's ability to self-report should be part of each
patient's medical record. Health professionals should teach patients and their families to
use these scales themselves to help in longitudinal pain assessment and continuity of
care. Patients with terminal illnesses should be encouraged to verbalize their
experiences of pain in their own words. The use of the "pain thermometer" has been
validated as a self-report instrument for pain intensity in patients with mild-to-moderate
cognitive impairment.[5,21,22]
For example, Eleanor describes her PHN as a "burning, needling pain" near her spine,
spreading out across her back on the right, beneath her axilla and around to her breast.
Her pain subsides sometimes, but rarely goes away altogether. Knowing the character
and location of her neuropathic pain allows her caregivers to pinpoint adjuvant pain
relief. In contrast, Eleanor's angina pain is "a deep heavy ache" in her chest. She notes
that it is intermittent and that it is stressful, because she never knows quite when to
expect it. By asking her to keep track of when her angina occurs, her caregivers are
able to predict more precisely when it may be triggered, and advise her accordingly,
perhaps reducing both severity and frequency.
A comprehensive evaluation of pain should include an assessment of the pain intensity,
character, frequency, onset, duration, and location as well as a detailed history of pain,
a physical and neurologic examination, a psychosocial assessment, and a diagnostic
evaluation that includes tests to determine the cause of pain. It is also important to take
into account common comorbidities, such as sleep disturbances and depression, which
can affect pain levels, suffering, and functioning.[21,22]
Florida Heart CPR*
End of life pain mgt
4
Patients sometimes complain of pain as a way of expressing other forms of suffering,
anxiety, or depression. When this is the case, psychosocial evaluation and intervention
will be more effective than analgesics. It is well established that attention and emotion
influence pain processing and perception, and conversely, inadequately managed pain
can lead to anxiety and depression.[7-9] Therefore, comprehensive assessment is
required to determine the optimal plan of care, as specific to pain etiology as possible.
Pain Types
Pain can usually be defined as nociceptive or neuropathic. Patients in the terminal stage
of an illness may often experience different mechanisms of pain operating
simultaneously. It is important to differentiate among different types of pain because the
type of treatment is largely dictated by the pain mechanism and its original source. [21] In
some conditions, pain appears to be caused by a complex mix of nociceptive and
neuropathic factors. In these cases, an initial nervous system dysfunction or injury may
trigger the neural release of inflammatory mediators and subsequent neurogenic
inflammation -- migraine headaches, for example, are most likely a mix of neuropathic
and nociceptive pain.
Nociceptive Pain
Nociceptive pain is typically the result of a musculoskeletal or visceral injury or disease
and includes somatic and visceral mechanisms. Primary afferent neurons receive
nociceptive input from peripheral nociceptors. Nociceptors are activated in response to
noxious stimuli, which can be thermal, chemical, or mechanical in character. Somatic
pain is characterized by aching, throbbing, stabbing, and/or a sensation of pressure. Its
source is skin, muscle, or bone. Visceral pain is characterized by gnawing, cramping,
aching, sharp, and/or stabbing sensations, and its source is the internal organs.
Nociceptive pain usually resolves when the initial tissue damage heals, and tends to
respond well to treatment with anti-inflammatory agents and opioids.[22-24]
Neuropathic Pain
Neuropathic pain is caused by lesions or physiologic changes in the nervous system,
and it is characterized by hypersensitivity either in the damaged area or in the
surrounding normal tissue. The pain is often triggered by an injury or disease, but there
may not be demonstrable damage to the nervous system other than the subjectively
reported sensory disturbance of pain. The pain frequently has qualities of burning,
numbness, tingling, touch sensitivity, sharp and shooting sensations (lancinating pain),
or electric shocks (see Figure 5). Persistent allodynia, which is pain resulting from a
nonpainful stimulus, such as a light touch, is a common characteristic of neuropathic
pain. Neuropathic pain tends to persist long after the initiating event has resolved.
Neural inflammation can change the actual structure of neural organization so that
stimuli that were once interpreted as touch become perceived as painful. Typical
examples include painful diabetic neuropathy, HIV/AIDS neuropathy, postherpetic
Florida Heart CPR*
End of life pain mgt
5
neuralgia, and cancer-induced as well as post-treatment cancer pain syndromes, such
as postmastectomy syndrome and radiation and chemotherapy neuropathies. [22,23,25]
Effects of Unrelieved Pain
There is significant evidence that inadequate pain relief hastens death by increasing
physiologic stress, potentially diminishing immunocompetence, reducing mobility,
increasing proclivities toward pneumonia and thromboembolism, and increasing the
work of breathing and myocardial oxygen requirements.[26] Pain may lead to a spiritual
despair and significant decrease in emotional well-being because the individual's quality
of life is impaired.[4,5] It is the professional and ethical responsibility of clinicians to focus
on and attend to adequate pain relief for their patients and to properly educate patients
and their caregivers about analgesic therapies.[27]
Returning to Eleanor, who has COPD, coronary artery disease, and PHN, it is clear that
discussions regarding care preferences (ie, advanced directives) are optimally done
prior to a medical crisis and while there is cognitive capacity for decision making.
However, under the current circumstances, a care planning meeting with the attending
clinician, consultant clinicians (eg, palliative care/hospice team), and designated
responsible family member is of paramount importance. Either pain must be adequately
controlled prior to discharge with a follow-up plan in place, or transfer to a skilled facility,
such as an inpatient palliative care/hospice unit (where pain management expertise and
focus can rapidly take place). Alternatively, with a prognosis of 6 months or less, if
Eleanor prefers to go home immediately, a hospice program with the ability to manage
her pain condition should be consulted. Regardless of setting, nonpharmacologic
approaches to pain control with titration of "first-line" agents for neuropathic pain
(anticonvulsants, topical local anesthetic, and opioids) should proceed with close
monitoring to balance therapeutic vs adverse effects.
Case 2: Sharon is a 70-year-old woman in the late stages of Alzheimer's disease with
severe osteoarthritis in her knees and spine. She lives with her married daughter and 2
grandchildren. Her daughter and a son living nearby provide her essential care, and,
until recently, she has remained active and ambulatory. She is beginning to experience
severe pain from her arthritis, manifest by grimacing, crying, and moaning. The current
caregivers are not always sure what she is expressing, but they understand that she is
in some distress and are eager to help alleviate it. They meet with their family doctor to
talk about options. Because Sharon is in the far-advanced stage of Alzheimer's disease,
the physician refers her to hospice for comprehensive care and support of her family.
During her initial evaluation, the family stresses that their primary goal is to make sure
that "Mom" is comfortable. The hospice nurse evaluates Sharon and determines that
she responds well to a variety of nonpharmacologic interventions. Her family members
express a willingness to use a variety of hands-on and nonpharmacologic techniques to
help Sharon live her last days relatively free of pain and suffering. Meanwhile, she is
started on a regimen of around-the-clock acetaminophen (1000 mg 4 times daily) with
the option for more potent pharmacologic therapies left open.
Florida Heart CPR*
End of life pain mgt
6
Nonpharmacologic Approaches to Pain Management in Palliative Care
An important aspect of any management strategy is the use of nonpharmacologic
treatments.[23,28] There are a variety of nonpharmacologic approaches to pain that have
been shown to be effective in alleviating pain for patients with advanced illness. These
include physical interventions, such as positioning and active or passive mobilization
(therapeutic exercise); techniques, such as TENS, massage, and heat/cold; and
complementary and alternative medicine techniques, music, and relaxation/imagery
exercises. Table 2 offers a list of some of the most common nonpharmacologic
interventions.
Table 2. Nonpharmacologic Approaches to Pain Management in Palliative Care
Intervention
Rehabilitation/physical therapy
Details




Massage


Physical, occupational, and speech therapy
are potentially beneficial in managing pain
Mobility may be improved by strengthening,
stretching, and the use of assisting devices
Home settings vary in their utility for a
debilitated person, as does the degree of
hands-on physical assistance that friends and
family can provide
The decision to use these modalities is made
on a case-by-case basis
Family members can be taught simple, safe
techniques of massage
Hospice programs can often provide trained,
certified massage therapists who are familiar
with the clinical issues faced by cancer and
noncancer patients with far-advanced disease
Transcutaneous/percutaneous
electrical nerve stimulation

Evidence exists to support the use of
percutaneous electrical nerve stimulation for
persistent low back pain and knee pain
Acupuncture

Popular complementary therapy for patients
with cancer and other end-stage pain
Many patients with cancer use acupuncture
when symptoms persist with conventional
treatments, or as a complement to their
ongoing treatments
Several researchers have found acupuncture
to be an effective antidepressant


Florida Heart CPR*
End of life pain mgt
7
Cognitive interventions

Studies show that acupuncture has a
significant positive effect on COPD, dyspnea
associated with end-stage cancer, and asthma

Some common cognitive interventions:
o
o
o
Music therapy
Psychological tools and strategies for
the purposes of self-regulating
emotions;
Distraction from noxious sensations and
thoughts; and
Methods for reducing negative attitudes

Involving patients in cognitive self-care may
improve mood and increase coping behaviors

Music effectively reduces anxiety and
improves mood for:
o
o
o
o




Medical and surgical patients;
Patients in intensive care units;
Patients undergoing procedures; and
In children as well as adults
Low-cost intervention
Often reduces chronic pain
Improves the quality of life, enhancing a sense
of comfort and relaxation
Music to caregivers may be a cost-effective
and enjoyable strategy for improving empathy,
compassion, and relationship-centered care
without interfering with technical aspects of
care
COPD = chronic obstructive pulmonary disease
The type of intervention, or combination of interventions, depends on the source and
severity of pain as well as the physical condition and receptivity of the patient. In an
investigation of the prevalence of complementary and alternative medicine use in an
end-of-life population, Tilden and colleagues,[29] through a series of phone interviews
with family caregivers of recently deceased, found that 53.7% of the deceased used
some kind of complementary therapy, were more likely to be younger with college
degrees and higher household incomes, and to have used 1 or more life-sustaining
treatment. Symptom relief was the most frequent reason given for complementary and
alternative medicine use.[29] Although a study by Weiner and Ernst[30] that reviewed
common complementary and alternative treatment modalities for the treatment of
Florida Heart CPR*
End of life pain mgt
8
persistent musculoskeletal pain found that the use of these modalities is increasing in
older adults, the study authors concluded that rigorous clinical trials examining efficacy
are still needed before definitive recommendations regarding the application of these
modalities can be made.
Aside from their objective efficacy, a medical sociologic study by Garnett [31] on the use
of complementary therapies by palliative care nurses sees these therapies as an
"emotional inoculation" that builds resiliency and an important bond between patient and
caregiver. Nonpharmacologic interventions often comfort the patient while involving and
empowering family and other caregivers. The necessity of feeling effective for
caregivers should not be overlooked -- it can have a direct effect on the experience of
the patient as well as the emotional survival of the family caregiver in particular. A study
by Keefe and colleagues[32] on the self-efficacy of family caregivers of cancer patients
found that caregivers who rated their self-efficacy as high reported much lower levels of
caregiver strain as well as lower negative mood and higher positive mood. Caregiver
self-efficacy in managing the patient's pain was related to the patient's physical wellbeing. When the caregiver reported high self-efficacy, the patient reported having more
energy, feeling less ill, and spending less time in bed.[32]
Rehabilitation and Physical Therapy
Functional rehabilitation and physical therapy techniques in appropriately selected
patients add to quality of life even in the face of limited life expectancy. Sharon is a
typical patient who responds well to nonpharmacologic pain intervention. A recent study
by Montagnini and colleagues[33] assessing the use of physical therapy in a hospitalbased palliative care setting found that a significant proportion demonstrated
improvement in function after 2 weeks. The study authors found that patients with a
diagnosis of dementia were most likely to show improvement in functional status and
concluded that physical therapy assessment and use were uncommon in the studied
group, but, when implemented, it benefited 56% of the patients.[33]
Massage
Research suggests that patients with cancer, particularly in the palliative care setting,
are increasingly using aromatherapy and massage. There is good evidence that these
therapies may be helpful for anxiety reduction for short periods. A study by Soden and
colleagues[34] was designed to compare the effects of 4-week courses of aromatherapy
with massage and massage alone on physical and psychological symptoms in patients
with advanced cancer. The study authors were unable to demonstrate any significant
long-term benefits of aromatherapy or massage in terms of improving pain control,
anxiety, or quality of life, but sleep scores improved significantly in both groups, and
there were statistically significant reductions in depression scores in the massage group
-- suggesting that patients with high levels of psychological distress respond best to
these therapies.[34]
Acupuncture and TENS
Florida Heart CPR*
End of life pain mgt
9
These modalities may be effective in selected patients based on meta-analyses of the
literature and findings of National Institutes of Health (NIH) consensus panels.[35] For
percutaneous procedures, appropriate cautions, skilled certified practitioners, and
fastidious aseptic techniques are required to protect patients and staff from untoward
adverse outcomes. Similarly, for therapies involving electrical stimulation, awareness of
implanted devices (pumps, stimulators, implantable cardioverter defibrillators, or
pacemakers) and precautions to prevent malfunction must be taken.
Cognitive Interventions
Simple psychological interventions can have a significant impact on pain. As an
example, Paqueta and colleagues[36] explored the idea that everyday emotion regulation
through a self-supporting maintenance or change in positive and negative emotions can
help reduce pain intensity in the hospitalized elderly. Emotion regulation was found to
be prospectively related to pain intensity for both overall emotion and anxiety-specific
regulation. The study authors suggest that promoting emotion regulation as a selfmanagement strategy could contribute to cost-effective pain management in general or
targeted elderly populations.[36]
Music Therapy
There is growing interest in the therapeutic use of music. The difficulties inherent in the
medical treatment of this population make the use of music, as a noninvasive
therapeutic modality, attractive.[37] Music is often used to enhance well-being, reduce
stress, and distract patients from unpleasant symptoms. Although there are wide
variations in individual preferences, music appears to exert direct physiologic effects
through the autonomic nervous system.[38]
Choosing the Best Approach
A combination of treatments is usually most effective when using nonpharmacologic
approaches to pain management. Similar to pharmacotherapy, multimodal approaches
offer the potential benefit of additive and synergistic effects. Because nonpharmacologic
therapies need to be tailored to individual likes, dislikes, and effectiveness, knowledge
of the various modalities, management of expectations, open-mindedness, and a "trialand-error" approach should be embraced.
The hospice nurse was able to offer Sharon's family a variety of hands-on and
alternative modalities that could be used in addition to pharmacologic interventions to
successfully comfort the patient. The nurse found that simple stretches and
strengthening and mobilization exercises were effective for reducing the stiffness that
was associated with Sharon's musculoskeletal disease. This helped both to relax the
patient and prevent the usual anxiety that is associated with getting her out of bed in the
morning and daily personal care, such as bathing and toileting. A simple TENS unit
appeared to ease the patient's knee pain. The nurse was also able to guide the family in
some interventions that reduced Sharon's anxiety and increased the family's sense of
Florida Heart CPR*
End of life pain mgt
10
involvement and effectiveness. They found that songs from her youth brought Sharon a
great deal of pleasure, and her son, a fan of the music, enjoyed spending listening time
with her. Physical contact often calmed Sharon, and the nurse trained Sharon's
granddaughter in simple massage techniques.
Case 3: Jerry is an 82-year-old man with metastatic colon cancer who has just returned
to his home in an assisted living facility postoperatively after a bowel resection. He sees
a geriatric nurse practitioner, in collaboration with a family physician, for ongoing
primary care. It has become clear that that there are widespread metastases, and his
oncologist agrees that the current goal of care is comfort only. Jerry is still ambulatory
and in the early stages of his terminal illness. No further chemotherapy or radiation
therapies are indicated, but the patient reports progressive abdominal pain, and
symptoms suggestive of intermittent bowel obstruction develop. Jerry refuses further
hospitalization and surgery, and prefers noninterventional therapies -- if at all possible.
A consulting pharmacist and medical director from the local hospice are asked to come
in and help the nurse practitioner choose the best pharmacotherapy for pain and bowelrelated signs and symptoms, including types of drugs, route of drug administration, and
the best way to minimize possible side effects. The explicit goals of care are a
comfortable, dignified death; crisis prevention; and self-determined life closure (no
prolongation of dying by medical intervention).
Drugs for Pain Relief in Palliative Care
Pharmacologic therapies for pain include nonopioids, opioids, adjuvant analgesics,
disease-modifying therapies, and (in some cases) interventional techniques. Intractable
pain and symptoms that are not responsive to basic therapeutic techniques, although
not common, must be treated appropriately and aggressively. In some highly selective
cases, palliative sedation may be warranted. A sound understanding of
pharmacotherapy for pain treatment allows the palliative care/hospice team to create a
comprehensive plan of care as well as recognize and assess medication-related
adverse effects, understand drug-drug and drug-disease interactions, and educate
patients and caregivers regarding appropriate medication usage. Recognition of the
limits of usual therapies and the ability to muster expert assistance are important skills.
This will ensure a comfortable process of dying for the well-being of the patient and for
the sake of those in attendance.
Genetic factors, pathologic processes, concurrent medication, and aging will all
influence drug response and disposition. However, there are also a variety of
nonmedical factors that influence responses to drug treatment in patients with faradvanced disease, including the social, environmental, and psychological milieu as well
as the general vulnerability of this population. Understanding the clinical pharmacology
of the drugs in question is essential for professional caregivers.[5] Commonly, there is a
need to use drugs for non-FDA-approved indications or routes of administration, simply
because randomized, controlled clinical trials have not been performed, due (usually) to
financial constraints. Rational polypharmacy (combining drugs with different
mechanisms of action to produce additive or synergistic effects and minimize adverse
Florida Heart CPR*
End of life pain mgt
11
effects) is often necessary, but there is a high potential for drug interactions, so close
monitoring is required.
The principles of effective symptom control are always paramount -- diagnose the
underlying cause of each symptom and tailor the treatment to individual circumstances
and clinical context. Keep in mind that normal pharmacokinetics and
pharmacodynamics may be considerably altered by end-stage disease states. For
example, in patients with chronic liver disease or hepatic metastases, drugs may
bypass hepatic metabolism altogether, increasing bioavailability. Similarly, renal
clearance is almost always diminished during the dying process, leading to the
accumulation of drug metabolites, some of which (eg, those of morphine) may be
toxic.[5,39,40]
Communicating With Patients, Families, and Other Healthcare Professionals
Communicating clearly about pharmacologic pain control with patients, families, and
other members of the palliative care/hospice team is essential to providing effective pain
management. It is important to be specific about the types of drugs that are available,
how they are likely to affect the patient, how they are to be administered, and how they
may interact with existing medications. Despite the importance of pain management at
the end of life, there are often substantial roadblocks to overcome in getting patients the
treatment that they need. Professional healthcare workers may have unsubstantiated
but strong beliefs about analgesic use, especially opioid use, that lead to
underprescribing.[41,42] There are several surveys that show that physicians, nurses, and
pharmacists express concerns about addiction, tolerance, and side effects of morphine
and related compounds.[43] These fears are pervasive among patients and family
members as well. Studies have suggested that these fears lead to undermedication and
increased pain intensity.[44] Concerns about being a "good" patient or belief in the
inevitability of cancer pain lead patients to hesitate in reporting pain. In these studies,
less educated and older patients were most likely to express these beliefs.[4]
Often, a physician or other providers may be reluctant to offer the patient direct and
objective information on his or her health, especially toward the end of life, seeking to
"soften the blow" by keeping the details vague. Most patients, however, prefer complete
information about his or her condition.[45,46] However, patients may wish to defer
decision making to the physician or family members.[45,47] Physicians have a
professional duty to determine patients' medical wishes. Pragmatically, this
responsibility may fall to the nurse or nurse practitioner, and there are tools, such as
simple card sorting, that can be used to facilitate this exchange,[48] for example, the 5card Control Preference Scale uses cards to portray different roles in treatment decision
making with a statement and a picture.[49]
Dispelling Common Myths About Pain Management
Understanding the barriers that are faced when treating pain can lead professionals to
better educate and counsel patients and their families.[32] Patients should be asked
Florida Heart CPR*
End of life pain mgt
12
whether they are concerned about addiction and tolerance (often described as
becoming "immune" to the drug).[50] At the end of life, patients may need to rely on
family members or other support persons to dispense medications. Studies suggest that
patients' pain experiences and family members' perceptions about them don't correlate
well, leading to inadequate provision of analgesia.[51,52] The interdisciplinary palliative
care/hospice team is essential in the communication effort, with nurses, social workers,
chaplains, physicians, volunteers, and others providing support in exploring the
meaning of pain and barriers to pain relief. Education, counseling, reframing, and
spiritual support are imperative.
Overview of Nonopioid and Opioid Therapy
This section provides a brief overview of both commonly used and newer
pharmaceutical agents available in the United States for the treatment of persistent pain
associated with advanced disease. Pain-relieving drugs can be categorized as
nonopioid analgesics, opioid analgesics, and the adjuvant analgesics. Detailed
knowledge of these classes of agents is necessary to provide quality palliative care,
although a comprehensive review is beyond the scope of this article.
There are several, possible methods of approaching pharmacologic pain management
for patients with advanced diseases. Patients may require several different medications
to deal with a variety of pain syndromes and disease- or treatment-related discomfort.
For expedient and thorough treatment, it is often wise to adopt a stepwise approach to
the use of pain medications. The World Health Organization (WHO) has developed a
simple, 3-step model for managing cancer pain that can be applied to many different
situations. It has been modified over time to adapt to the evolving fields of pain and
palliative medicine (see Figure 6). This revised approach recommends that mild pain (13 on a numerical analogue scale) should be treated with nonopioid pain relievers, such
as aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs (NSAIDs), with or
without adjuvant therapy. Higher pain intensities indicate the use of nonopioid
analgesics along with opiate derivatives, such as codeine, hydrocodone, or tramadol.[25]
If pain is not relieved, then titration of opioids, such as morphine, hydromorphone, and
fentanyl, in combination with nonopioid analgesics and adjuvants is indicated.
Refractory pain syndromes will often require more invasive techniques, such as spinal
opioids, nerve block, or neurostimulation.[1]
Nonopioid Analgesics
Acetaminophen. Acetaminophen has been determined to be one of the safest
analgesics for long-term use in the management of mild pain or as a supplement in the
management of more intense pain syndromes. It is especially useful in the management
of nonspecific musculoskeletal pain or pain associated with osteoarthritis, but should be
considered an adjunct to any chronic pain regimen. It is often forgotten or overlooked
when severe pain is being treated, but it can be quite effective as a "coanalgesic." It is
important to take into account acetaminophen's limited anti-inflammatory effect and its
hepatic effects. Reduced doses or avoidance of acetaminophen is recommended for
Florida Heart CPR*
End of life pain mgt
13
patients with renal insufficiency or liver failure, particularly in individuals with significant
alcohol use.[53,54]
NSAIDs. NSAIDs reduce the biosynthesis of prostaglandins by inhibiting
cyclooxygenase (COX) and the cascade of inflammatory events that cause, amplify, or
maintain nociception. NSAIDs also appear to directly affect the peripheral and central
nervous systems. COX has been identified in spinal cord neurons, and may play a role
in the development of neuropathic pain, but these agents do not appear to be useful in
the treatment of neuropathic pain.[25] The "classic" NSAIDs (eg, aspirin or ibuprofen) are
relatively nonselective in their inhibitory effects on the enzymes that convert arachidonic
acid to prostaglandins, so gastrointestinal ulceration, renal dysfunction, and impaired
platelet aggregation are common.[4] The COX-2 selective NSAIDs rofecoxib (Vioxx) and
valdecoxib (Bextra) are now off the market, and, due to potential problems and
concerns with gastrointestinal bleeding and thrombosis, celecoxib (Celebrex) should be
used with caution in high-risk palliative care patients.[55]
NSAIDs are useful in treating many pain conditions mediated by inflammation, including
those caused by cancer.[58,59] These agents cause minimal nausea, constipation,
sedation, or effects on mental function, although there is evidence that their use can
impair short-term memory in older patients.[58] These agents may be very useful for
moderate-to-severe pain control, either alone or as an adjunct to opioid analgesic
therapy. Adding NSAIDs to an opioid regime may allow a reduced opioid dose when
sedation, obtundation, confusion, dizziness, or other central nervous system effects of
opioid analgesic therapy alone become problematic.[59] Extended-release formulations
are likely to increase compliance and adherence.[25] As with acetaminophen, decreased
renal function and liver failure are relative contraindications for NSAID use. Platelet
dysfunction or other potential bleeding disorders also contraindicate use of the
nonselective NSAIDs due to their inhibitory effects on platelet aggregation, a clear
advantage of the coxib class of NSAIDs. If NSAIDs are effective, but there is need for
prolonged use or there is a history of gastrointestinal complications, proton pump
inhibitors can be given to lower the risk of gastrointestinal bleeding.[60]
Opioid Analgesics
Opioid analgesics are the most useful agents for the treatment of pain associated with
advanced disease. They reduce pain-producing signals and perception throughout the
nervous system, regardless of the pathophysiology of the pain.[61] Opioids exist in 3
classes -- pure agonists, mixed agonist-antagonist, and pure antagonists.[39] They are
classified according to their interaction with the 3 major opioid receptor types. Pure
agonists, which interact with (mu) receptors in the brain and spinal cord, are generally
preferred for managing moderate-to-severe pain, and have been shown to reduce pain
in a number of neuropathic pain syndromes, contrary to previous thinking. [62] Opioids
can also be used to treat dyspnea and as an anesthetic adjunct. There are few, if any,
indications for the mixed agonist-antagonist agents. The pure antagonists are used to
treat acute overdose and, in selected cases, as a means of treating or preventing
opioid-induced bowel dysfunction. The opioids used most commonly in palliative care
Florida Heart CPR*
End of life pain mgt
14
are morphine, hydromorphone, fentanyl, oxycodone, and methadone. A sustainedrelease form of oxymorphone is in the approval stage and may add to this growing
formulary.
The only absolute contraindication to the use of an opioid is a history of a
hypersensitivity reaction (eg, rash, wheezing, and edema). Allergic reactions are almost
exclusively limited to the morphine derivatives, and the prevalence of true allergic
reactions to synthetic opioids is much lower. There is significant inter- and
intraindividual variation in clinical responses to the various opioids, so dose titration is
the best approach to initial management. Idiosyncratic responses may require trials of
different agents in order to determine the most effective drug and route of delivery for
any given patient. Table 4 lists more specific suggestions regarding optimal use of
opioids.
Opioid analgesics may accumulate toxic metabolites over time, especially when drug
clearance and elimination decrease as disease progresses and organ function
deteriorates.[63] Use of meperidine is specifically discouraged for chronic pain
management due to its neurotoxic metabolite, normeperidine.[25] Use of propoxyphene
(eg, Darvocet-N 100) is also discouraged due to the active metabolite
norpropoxyphene, its weak analgesic efficacy, and the significant acetaminophen dose
found in some formulations.[64] The mixed agonist-antagonist agents, typified by
butorphanol, nalbuphine, and pentazocine, are not recommended for the treatment of
chronic pain. They have limited efficacy, and their use may cause an acute abstinence
syndrome in patients using pure agonist opioids.[39,65]
Morphine. Morphine, the prototype agonist, is considered the "gold standard" of opioid
analgesics and is used as a measure for dose equivalence.[39,64] Although some
patients cannot tolerate morphine due to pruritus, headache, dysphoria, or other
adverse effects, common initial dosing effects, such as sedation and nausea, often
resolve within a few days.[4] It is best to anticipate these adverse effects, especially
constipation, nausea, and sedation, and prevent or treat appropriately (see below).
Morphine-3-glucuronide, a metabolite of morphine, may contribute to myoclonus,
seizures, and hyperalgesia, particularly when patients cannot clear the metabolite due
to renal impairment.[63,66] Side effects and metabolite effects can be differentiated over
time: Side effects generally occur soon after the drug is absorbed, whereas metabolite
effects are generally delayed by several days. If adverse effects exceed the analgesic
benefit of the drug, convert to an equianalgesic dose of a different opioid. Because
cross-tolerance is incomplete, reduce the calculated dose by one third to one half and
titrate upward based on the patient's pain intensity scores.[4]
Morphine's bitter taste may be prohibitive, especially if "immediate-release" tablets are
left in the mouth to dissolve. In this case, several options are available. One available
type of long-acting morphine comes in a capsule that can be opened, releasing small
pellets that can be mixed in applesauce or other soft food.[67] Oral morphine solution can
be swallowed, or small volumes (0.5-1 mL) of a concentrated solution (eg, 20 mg/mL)
Florida Heart CPR*
End of life pain mgt
15
can be placed in the mouth of patients whose voluntary swallowing capabilities are
significantly limited.[68]
Fentanyl. Fentanyl is a lipophilic opioid that can be administered parenterally, spinally,
transdermally, transmucosally, and nebulized for the management of dyspnea. [4]
Because of its potency, dosing is usually conducted in micrograms. It should be noted
that on July 15, 2005, the FDA issued a public health advisory to alert healthcare
professionals, patients, and their caregivers of reports of death and other serious side
effects from overdoses of fentanyl in patients using transdermal fentanyl (Duragesic) for
pain control.[69] Careful fentanyl dosing is particularly important in older patients; a
recent study of transdermal fentanyl in postoperative patients found that absorption was
significantly delayed in men 64-82 years of age compared with men 25-38 years of
age.[70]
In consideration of the aforesaid cautions, transdermal fentanyl, often called the fentanyl
patch, is particularly useful when patients cannot swallow, do not remember to take
medications, or experience adverse effects from other opioids.[71] Opioid-naive patients
should begin with titrated immediate-release opioids to establish the needed 24-hour
dose of opioid before determining that the lowest available dose, currently a 12mcg/hour patch, can be tolerated. Patients should be monitored by a responsible
caregiver for the first 24-48 hours of therapy until steady-state blood levels are reached.
Transdermal fentanyl may not be appropriate for patients with fever, diaphoresis,
cachexia, morbid obesity, and ascites, all of which may have a significant impact on the
absorption, blood levels, and clinical effects of the drug.[72,73]
Some patients experience reduced analgesic effects within 48 hours of applying a new
patch. If so, determine whether a higher dose can be tolerated with increased duration
of effect or whether a more frequent (every 48 h) patch change is the better alternative.
Under most circumstances, breakthrough pain medications should be available to
patients using continuous-release opioids, such as the fentanyl patch. There are
several, novel transdermal fentanyl delivery systems under development, including ones
that allow bolus dosing. There are insufficient data or experience to make
recommendations about their relative safety or efficacy at this time.
Oral transmucosal fentanyl citrate (Actiq) is composed of fentanyl on an oral applicator
("lollipop") to provide rapid absorption of the drug. This formulation of fentanyl is
particularly useful for breakthrough pain.
Oxycodone. Oxycodone is a synthetic opioid available in a long-acting formulation
(OxyContin), as well as immediate-release tablets (alone or with acetaminophen) and
liquid. It is approximately as lipid-soluble as morphine, but has better oral absorption.[74]
Side effects appear to be similar to those experienced with morphine, but one study
comparing the 2 formulations in patients with advanced cancer found that oxycodone
was less likely to cause nausea and vomiting.[75] Despite significant media attention to
oxycodone and its role in opioid abuse, there is no basis to infer that it is inherently
"more addicting" than other opioids used in palliative care. Because of this attention,
Florida Heart CPR*
End of life pain mgt
16
however, several states have restricted the numbers of tablets that can be distributed to
an individual in a month.
Methadone. Methadone has several characteristics that make it useful in the
management of severe, chronic pain.[39,76,77] Methadone has a half-life of 24-36 hours
with a much longer terminal half-life, allowing for prolonged dosing intervals. Methadone
is an N-methyl-D-aspartate (NMDA) receptor antagonist, which may be of particular
benefit in neuropathic pain.[78,79] Methadone is much less costly than comparable doses
of proprietary continuous-release formulations, making it potentially more available for
patients without sufficient financial resources for more expensive drugs.
Despite these advantages, much is unknown about the appropriate dosing ratio
between methadone and morphine, as well as the safest and most effective time course
for conversion from another opioid to methadone.[4] Current data suggest that the dose
ratio increases as the previous dose of oral opioid equivalents increases, and, although
the long half-life is an advantage, it also increases the potential for drug accumulation
prior to achieving steady-state blood levels.[80] There may be a risk of oversedation and
respiratory depression after 2-5 days of treatment with methadone. Close monitoring of
these potentially adverse or even life-threatening effects is required.[25,39] Myoclonus
has been reported with methadone use, and recent studies suggest that high doses of
methadone may lead to life-threatening QT interval prolongation (although it is not clear
whether this is due to the methadone or preservatives in the parenteral formulation).[4]
Patients currently receiving methadone as part of a maintenance program for addictive
disease often develop cross-tolerance to opioids and require higher doses than opioidnaive patients.[81] Prescribing methadone for addictive disease requires a special
license in the United States, so prescriptions for methadone to manage pain in palliative
care should specify "for pain."
Hydromorphone. Hydromorphone (Dilaudid) is a synthetic opioid that can be a useful
alternative to morphine. It is available in oral tablets, liquids, suppositories, and
parenteral formulations, but the only long-acting formulation was recently recalled by the
FDA due to interactions with alcohol that could lead to excessively rapid drug
release.[39,82] As a synthetic opioid, hydromorphone can be useful if there is inadequate
pain control or when patients experience true allergic responses to morphine or
intolerable side effects occur. The metabolite hydromorphone-3-glucuronide may lead to
the same opioid neurotoxicity seen with morphine metabolites: myoclonus,
hyperalgesia, and seizures.[83] This is particularly likely in patients with renal
dysfunction.[84,85]
Other Opioids. Codeine, hydrocodone, levorphanol, oxymorphone, and tramadol are
other opioids available in the United States for treatment of pain.
Florida Heart CPR*
End of life pain mgt
17
Routes for Administering Opioids
The oral route is generally preferred when patients are capable and enteral absorption
is not problematic. In the palliative care setting, alternative routes of administration must
be available for patients who can no longer swallow or when other dynamics preclude
the oral route. These include transdermal, transmucosal, rectal, vaginal, topical,
epidural, and intrathecal. In a study of cancer patients at 4 weeks, 1 week, and 24 hours
before death, over half of the patients required more than 1 route of opioid
administration. As patients approached death and oral use diminished, the use of
intermittent subcutaneous injections and intravenous or subcutaneous infusions
increased.[11]
Enteral feeding tubes can be used to access the gut when patients can no longer
swallow. The rectum, stoma, or vagina can be used to deliver medication, although
fecal contents, mucosal dryness, thrombocytopenia, or painful lesions may preclude the
use of these routes. For morphine, commercially prepared suppositories, compounded
suppositories, or microenemas can be used to deliver the drug directly to the rectum or
stoma.[86] Sustained-release morphine tablets have been used rectally, with resultant
delayed time to peak plasma level and approximately 90% of the bioavailability
achieved by oral administration. Because the vagina has no sphincter, a tampon
covered with a condom or an inflated urinary catheter balloon may be used to prevent
early discharge of the drug.[87] Although useful, the rectal or vaginal routes may be
unacceptable to many patients and their caregivers, especially when the patient is
obtunded or unable to assist.[5]
Parenteral administration in palliative care is usually limited to subcutaneous and
intravenous delivery because repeated intramuscular opioid delivery is excessively
noxious. The intravenous route provides rapid drug delivery but requires vascular
access, which may not be easily obtained or maintained in a home or long-term care
setting. In the absence of intravenous access, it must be remembered that
subcutaneous boluses, although effective, have a slower onset and lower peak effect
when compared with intravenous boluses.[4] Subcutaneous infusions as much as 10
mL/hour are usually absorbed, although most patients tolerate 2-3 mL/hour with least
difficulty.[88,89]
Intraspinal routes, including epidural or intrathecal delivery, may allow administration of
drugs, such as opioids, local anesthetics, and/or a-adrenergic agonists. A recent
randomized, controlled trial demonstrated benefit for cancer patients experiencing
pain.[90] However, the equipment used to deliver these medications is complex, requiring
specialized knowledge for healthcare professionals and potentially greater caregiver
burden. Risk of infection and other complications along with upfront and maintenance
costs are significant concerns when contemplating high-technology procedures.
Selection should be based on greater than 6 months life expectancy for implanted
programmable pumps, and adequate organizational infrastructure to manage these
devices should be in place.
Florida Heart CPR*
End of life pain mgt
18
Adjuvant Therapies
The term "adjuvant analgesics" is often used synonymously with "coanalgesics," "painmodifying drugs," and similar descriptives. A wide variety of nonopioid medications from
several pharmacologic classes have been demonstrated to reduce pain caused by
various pathologic conditions (eg, tricyclic antidepressants) or to modify the ongoing
disease process in a way that specifically reduces pain (eg, bisphosphonates). Under
most circumstances, these drugs are indicated for the treatment of severe neuropathic
pain or bone pain, and opioid analgesics are used concurrently to provide adequate
pain relief. Typical adjuvants include tricyclic antidepressants, serotonin-norepinephrine
reuptake inhibitor (SNRI) antidepressants, anticonvulsants, corticosteroids, and other
disease-modifying drugs, such as bisphosphonates for metastatic bone pain.
Antidepressants. The analgesic effect of tricyclic antidepressants appears to be
related to inhibition of norepinephrine and serotonin reuptake, making these
neurotransmitters more available within central nervous system pain inhibitory
pathways. There are many significant, controlled clinical trials for several pain
conditions, and a recent consensus panel listed tricyclic antidepressants as 1 of 5 firstline therapies for neuropathic pain.[91,92] The significant side effects, especially in older
patients, limit the use of these agents in palliative care, but their sleep-enhancing and
mood-elevating effects may be beneficial enough to outweigh their disadvantages. [93]
The newer mixed SNRIs-selective serotonin reuptake inhibitors (SSRIs), such as
venlafaxine (Effexor) and duloxetine (Cymbalta), may offer some of the advantages of
tricyclic antidepressants without the anticholinergic side effects.[39]
Anticonvulsants. The older anticonvulsants, such as carbamazepine and clonazepam,
relieve pain by blocking sodium channels.[93] These compounds are very useful in the
treatment of neuropathic pain, especially pain with episodic, lancinating qualities.
Gabapentin seems to have several different mechanisms of action, although calcium ion
channel blockade is thought to be its main pain-inhibiting mechanism.[94,95]
The analgesic doses of gabapentin reported to relieve pain in non-end-of-life pain
conditions ranged from 900 mg/day to 3600 mg/day in divided doses.[4] A common
reason for inadequate relief is failure to titrate upward after prescribing the usual starting
dose of 100 mg by mouth 3 times daily. Additional evidence supports the use of
gabapentin in neuropathic pain syndromes seen in palliative care, such as thalamic
pain, pain due to spinal cord injury, cancer pain, and restless legs syndrome and HIVassociated sensory neuropathies.[23,95,96] Withdrawal from gabapentin should be gradual
to prevent possible seizures.[97] Lamotrigine has been effective in HIV-associated
neuropathy, diabetic neuropathy, and poststroke pain. It requires slow titration and may
have prohibitive side effects, such as Steven-Johnson syndrome and severe rash.[23]
Newer anticonvulsants that have been used successfully in treating neuropathies
include levetiracetam, tiagabine, and oxcarbazepine, but no randomized, controlled
clinical trials are available.[23]
Florida Heart CPR*
End of life pain mgt
19
Corticosteroids. Corticosteroids are particularly useful for neuropathic, visceral, and
bone pain syndromes, including plexopathies and pain associated with stretching of the
liver capsule due to metastases.[98,99] Dexamethasone produces the least amount of
mineralocorticoid effect, making it the least toxic choice. Dexamethasone is available in
oral, intravenous, subcutaneous, and epidural formulations. The standard dose is 16-24
mg/day and can be administered once daily due to the long half-life of this drug, but
divided doses are usually used to mitigate high-dose toxic effects, such as psychosis
and severe blood sugar abnormalities in diabetic patients. Doses as high as 100 mg
may be given with severe pain crises, similar to the doses used in acute neurologic
emergencies. Intravenous bolus doses should be administered over several minutes to
reduce untoward reactions, such as burning sensations.
Local Anesthetics. Local anesthetics are useful for relieving neuropathic pain. They
can be given orally, topically, intravenously, subcutaneously, or spinally. [23,100] Mexiletine
has been reported to be useful when anticonvulsants and other adjuvant therapies have
failed. Doses start at 150 mg/day and increase to levels as high as 900 mg/day in
divided doses.[101,102] Pretreatment electrocardiogram evaluation is recommended to
evaluate for conduction blocks that can be exacerbated by oral local anesthetics. Local
anesthetic gels and patches have been used to prevent the pain that is associated with
needlestick and other minor procedures. Both gel and patch (Lidoderm) versions of
lidocaine have been shown to reduce the pain of postherpetic neuralgia. [103] Intravenous
lidocaine at 1-5 mg/kg (maximum, 500 mg) administered over 1 hour, followed by a
continuous infusion of 1-2 mg/kg/hour, has been reported to reduce intractable
neuropathic pain in patients in inpatient palliative care and home hospice settings. [23]
Epidural or intrathecal lidocaine or bupivacaine delivered with an opioid can reduce
neuropathic pain.[104]
Bisphosphonates. Bisphosphonates inhibit osteoclast-mediated bone resorption and
alleviate pain related to metastatic bone disease and multiple myeloma, reduce the
incidence of pathologic fractures, and are used to treat tumor-related hypercalcemia.[105]
In patients with breast cancer and multiple myeloma, zoledronic acid has demonstrated
improved safety and efficacy compared with pamidronate.[106,107] Similarly, there
appears to be more sustained pain relief with zoledronic acid compared with other
bisphosphonates in patients with metastatic prostate cancer.[108] Clinical trials in patients
with lung and renal cell carcinoma have also shown therapeutic benefit from regular
infusions of zoledronic acid.[109]
Calcitonin. Subcutaneous calcitonin may be effective in the relief of neuropathic or
bone pain, although studies are inconclusive.[110] The nasal form of this drug may be
more acceptable in end-of-life care when other therapies are ineffective. Usual doses
are 100-200 IU/day subcutaneously or nasally.
Chemotherapy and Radiation Therapy. Palliative chemotherapy is the use of
antitumor therapy to relieve the symptoms that are associated with malignancy. Patient
goals, performance status, sensitivity of the tumor, and potential toxicities must be
considered.[4] Examples of symptoms that may improve with chemotherapy include
Florida Heart CPR*
End of life pain mgt
20
relief of chest wall pain from reduced tumor ulceration through the use of hormonal
therapy in breast cancer. Similarly, newer agents, such as docetaxel, reduce pain and
improve quality of life in hormone-refractory prostate cancer, and topotecan and
epidermal growth factor receptor inhibitors accomplish similar results for patients with
lung cancers.[111-113]
Radiation therapy is also a highly useful adjunct to control pain from bone metastasis
and pressure-inducing and ulcerative malignancies. Single-fraction and
hypofractionated regimens are proving to be effective in very sick patients and those
with limited life expectancy in whom the opportunity costs of multiple treatment sessions
are untenable.[114,115] These therapies are often underutilized in hospice/palliative care,
and they should be considered for any patient with a life expectancy of more than a few
weeks.[116]
Other Adjunct Analgesics. Topical capsaicin has been shown to be useful in relieving
the pain that is associated with postmastectomy syndrome, postherpetic neuralgia, and
postsurgical neuropathic pain in cancer.[98] A burning sensation experienced by patients
is a common reason for discontinuing therapy.
Baclofen, a skeletal muscle relaxant, is also useful for the relief of spasm-associated
pain, and it may be helpful in the treatment of intractable hiccups, which can be painful
and cause sleep disturbance.[117] Doses begin at 10 mg/day, increasing every few days.
Feelings of weakness and confusion or hallucinations often occur with doses above 60
mg/day. Slow downward titration is necessary to prevent withdrawal-related seizures.
Calcium channel blockers are believed to provide pain relief in certain pain syndromes
as well. For instance, nifedipine 10 mg orally may be useful to relieve ischemic or
neuropathic pain syndromes.[118,119] There are few randomized, controlled clinical trials
to support these mostly anecdotal findings.
Beginning Therapy, Adding or Changing Drugs, and Breakthrough Pain
Application of practical and mechanism-based approaches, coupled with contextappropriate follow-up, will optimize drug and other palliative therapies. The "best first
choice" and subsequent timing of opioid rotation will depend on patient-specific medical,
psychological, and social considerations and a sound knowledge of opioid
pharmacotherapy. Titration and combining drugs that may provide additive or
synergistic effects should proceed along rational lines, based on the pharmacokinetics
and monitored pharmacodynamics of the drugs. Frail patients and those with pain crises
may require observation in a monitored setting in order to provide safe and effective
relief within an acceptable time frame.
Transitory flares of pain, or "breakthrough pain," can be expected both at rest and
during movement. If breakthrough pain lasts longer than a few minutes, rescue doses of
the patient's current analgesics may provide relief.[25] In patients without parenteral
access, oral transmucosal fentanyl may be useful for rapid episodic pain relief or during
Florida Heart CPR*
End of life pain mgt
21
a brief but painful dressing change. Adults should start with the 200-mcg dose and
monitor efficacy, advancing to higher dose units as needed.[120] Clinicians must be
aware that, unlike other breakthrough pain drugs, the around-the-clock dose of opioid
does not predict the effective dose of oral transmucosal fentanyl. Pain relief can usually
be expected in about 5-10 minutes after beginning use. Patients should use oral
transmucosal fentanyl citrate over a period of 15 minutes because more active sucking
will result in more swallowing and less transmucosal absorption.
Because misunderstandings lead to undertreatment, all clinicians involved in the care of
patients with chronic pain must be able to differentiate the clinical conditions of
tolerance, physical dependence, and addiction that come with the use of opioids. It is
also critically important to be aware that titration of opioid analgesics to affect pain relief
is rarely associated with induced respiratory depression and iatrogenic death. The most
compelling evidence suggests that inadequate pain relief hastens death by increasing
physiologic stress, decreasing immunocompetence, diminishing mobility, increasing the
potential for thromboembolism, worsening respiratory effort and thus placing the patient
at risk for pneumonia, and increasing myocardial oxygen requirements. In a recent
survey of high-dose opioid use (> 299 mg of oral morphine equivalents) in a hospice
setting, there was no relationship between opioid dose and survival.[121]
Minimizing and Managing Adverse Effects
There are a variety of adverse effects that drugs for pain can cause patients in palliative
care. The normal side effects associated with pain relief medications are often
exacerbated by changes in metabolism caused by end-stage disease, polypharmacy
associated with old age, and other factors. Below are some of the more common
adverse effects seen for these patients, and an overview of possible approaches to
preventing or alleviating them.
Constipation. Patients in palliative care frequently experience constipation, in part due
to opioid therapy.[44] Always begin a prophylactic bowel regimen when commencing
opioid analgesic therapy. Avoid bulking agents, such as psyllium, because these tend to
increase desiccation time in the large bowel, and debilitated patients can rarely take in
sufficient fluid to facilitate the action of bulking agents. Instead use cost-effective and
palatable products, such as senna tea and fruit.[39] If this is ineffective at creating regular
laxation, then prescription therapies are indicated (eg, bisacodyl, senna derivatives,
etc). Tables listing recommended regimens are readily available in clinical guidelines
and texts.
Sedation. Excessive sedation may occur with the initial doses of opioids. If sedation
persists after 24-48 hours and other correctable causes have been identified and
treated, the use of psychostimulants may be beneficial. These include
dextroamphetamine 2.5-5 mg by mouth every morning and midday or methylphenidate
5-10 mg by mouth every morning and 2.5-5 mg midday (although higher doses are
frequently used, and use later in the day may be required for wakefulness throughout
the evening hours, if desired).[4] Adjust both the dose and timing to prevent nocturnal
Florida Heart CPR*
End of life pain mgt
22
insomnia, and monitor for undesirable psychotomimetic effects (such as agitation,
hallucinations, and irritability). Once-daily dosing of modafinil, a newer agent approved
to manage narcolepsy, has been reported to relieve opioid-induced sedation.[122]
Respiratory Depression. Respiratory depression is rarely a clinically significant
problem for opioid-tolerant patients who are in pain.[39] When respiratory depression
occurs in a patient with advanced disease, the cause is usually multifactorial. [123,124]
When depressed consciousness occurs along with a respiratory rate less than 8/minute
or hypoxemia (O2 saturation less than 90%) associated with opioid use, slow, cautious
titration of naloxone should be instituted (0.4 mcg every 3-5 minutes while providing
respiratory support and supplemental oxygen). Excessive administration may cause
abrupt opioid reversal with pain and autonomic crisis.
Nausea and Vomiting. Nausea is common and vomiting is an occasional adverse
effect associated with opioids due to activation of the chemoreceptor trigger zone in the
medulla, vestibular sensitivity, and delayed gastric emptying, but habituation occurs in
most cases within several days.[125] Assess for other treatable causes. In severe cases
or when nausea and vomiting are not self-limited, pharmacotherapy is indicated.
Usually, low doses of an H1 blocker (eg, diphenhydramine) are all that is required while
the patient habituates to this unpleasant side effect. If there is no relief within a few
days, a different opioid is recommended; also consider transdermal rather than enteral
therapy.
Myoclonus. Myoclonic jerking can occur with high-dose opioid therapy.[39] If myoclonus
develops, switch to an alternate opioid, especially if using morphine. Evidence suggests
that this symptom is associated with metabolite accumulation, particularly in the face of
renal dysfunction.[4] A lower relative dose of the substituted drug may be possible, due
to incomplete cross-tolerance. Clonazepam 0.5-1 mg by mouth every 6-8 hours, to be
increased as needed and tolerated, may be useful in treating myoclonus in patients who
are still alert, able to communicate, and take oral preparations.[126] Lorazepam can be
given sublingually if the patient is unable to swallow. Otherwise, parenteral
administration of diazepam is indicated if symptoms are distressing. Grand mal seizures
associated with high-dose parenteral opioid infusions have been reported and may be
due to preservatives in the solution.[127] Preservative-free solutions should be used
when administering high-dose infusions.
Pruritus. Pruritus can occur with most opioids, although it appears to be most common
with morphine. Fentanyl and oxymorphone may be less likely to cause histamine
release. Most antipruritus therapies cause sedation, so the patient must see this as an
acceptable trade-off. Antihistamines (such as diphenhydramine) are the most common
first-line approach to this opioid-induced symptom when treatment is indicated.
Ondansetron and paroxetine have been reported to be effective in relieving opioidinduced pruritus, but no randomized, controlled studies exist.[128,129]
After examination and consultation, it is determined that Jerry can continue to live in the
assisted living facility, attended to by home-based hospice staff. Treatment proceeded
Florida Heart CPR*
End of life pain mgt
23
with subcutaneous administration of octreotide and hydromorphone to relieve bowel
symptoms and provide analgesia on an as-needed basis. In this way, the
unpleasantness of nasogastric suctioning, nausea, and vomiting was avoided, and the
patient was able to die in a manner consistent with his preferences.
Summary
In summary, effective pain management in advanced medical illness and at the end of
life is a critical component of quality medical care to ensure a dignified, safe, and
comfortable dying. To quote Sir William Osler, the "father" of modern medicine, "The
study of morbid anatomy combined with careful clinical observations has taught us to
recognize our limitations and to accept the fact that a disease itself may be incurable
and that the best we can do is to relieve symptoms and make the patient
comfortable.[130]"
Principles to help improve this important domain of clinical care can be summarized with
the following key points regarding pharmacotherapy for the relief of pain in far-advanced
illness.
Principles of Effective Pain Management

Determine the etiology of pain and the social and prognostic circumstances that
will affect the pain experience and pain therapy.

Focus on discernible clinical end points:
o
o
o
o
o
o
Pain reduction
Functional capacities
Mood
Sleep
Relationships
Pleasure in living

Match the mechanism of pain with the class of drug whenever possible; initiate
therapy and adjust dose according to therapeutic response, side effects, and
known pharmacokinetics of the drug.

Anticipate and monitor for adverse effects:
o
o
Prevent side effects
Actively treat side effects

Acetaminophen should be the first consideration in the treatment of mild-tomoderate pain of musculoskeletal origin.

Use adjunctive drug therapies, especially for neuropathic pain.
Florida Heart CPR*
End of life pain mgt
24

Opioid analgesic drugs are often necessary to relieve moderate-to-severe pain,
and long-acting or sustained-release analgesic preparations should be used for
continuous pain.

Breakthrough pain should be identified and treated by the use of fast-onset,
short-acting preparations.

Lastly, and perhaps most importantly, know your limits. When a patient is not
responding to therapy, be prepared to consult with someone who has more
training, expertise, and experience.
Original content for this activity was supported by VistaCare and National Hospice and
Palliative Care Organization.
References
1. Fine PG. The evolving and important role of anesthesiology in palliative care.
Anesth Analg. 2005;100:183-188.
2. Ng K, von Gunten CF. Symptoms and attitudes of 100 consecutive patients
admitted to an acute hospice/palliative care unit. J Pain Symptom Manage.
1998;16:307-316.
3. Caraceni A, Weinstein SM. Classification of cancer pain syndromes. Oncology
(Williston Park). 2001;15:1627-1640, 1642; discussion 1642-1623, 1646-1627.
4. Paice JA, Fine PG. Pain at the end of life. In: Ferrell BR, Coyle N, eds. Oxford
Textbook of Palliative Nursing. 2nd ed. New York: Oxford University Press; 2001.
5. Doyle D, Hanks G, Cherny NI, Calman K, eds. Oxford Textbook of Palliative
Medicine. 3rd ed. Oxford, United Kingdom: Oxford University Press; 2003.
Florida Heart CPR*
End of life pain mgt
25
Florida Heart CPR*
End of Life Pain Management Assessment
1. Assessing pain in patients approaching the end of life requires a _____
evaluation.
a. Thorough
b. Quick
c. Medical
d. Multifactorial
2. The prevalence of pain in the terminally ill varies by diagnosis and ______.
a. Age
b. Weight
c. Perception
d. Demographics
3. The primary source of information in pain assessment should be ______.
a. Physical exam
b. Diagnosis
c. Prognosis of a disease
d. Patient’s self report
4. This is typically the result of a musculoskeletal or visceral injury or disease and
includes somatic and visceral mechanisms.
a. Neuropathic pain
b. Nociceptive pain
c. Both A and B
d. Neither A nor B
5. This is caused by lesions or physiologic changes in the nervous system, and it is
characterized by hypersensitivity either in the damaged area or in the
surrounding normal tissue.
a. Neuropathic pain
b. Nociceptive pain
c. Both A and B
d. Neither A nor B
6. This is an example of a nonpharmacologic approach to pain management:
a. Morphine
b. Music therapy
c. Acupuncture
d. B and C
7. Research suggests that patients with cancer, particularly in the palliative care
setting, are increasingly using aromatherapy and _____.
Florida Heart CPR*
End of life pain mgt
26
a.
b.
c.
d.
Yoga
Meditation
Massage
Herbal medicines
8. For percutaneous procedures ________ are required to protect patients and staff
from untoward adverse outcomes.
a. appropriate cautions
b. skilled certified practitioners
c. fastidious aseptic techniques
d. all of the above
9. The interdisciplinary palliative care/hospice team is essential in the
communication effort, with nurses, social workers, chaplains, physicians,
volunteers, and others providing support in exploring the meaning of pain and
barriers to pain relief. Education and _______ are imperative.
a. Counseling
b. Reframing
c. Spiritual support
d. All of the above
10. _____ the prototype agonist, is considered the "gold standard" of opioid
analgesics and is used as a measure for dose equivalence.
a. Morphine
b. Fentanyl
c. Oxycodone
d. Methadone
Florida Heart CPR*
End of life pain mgt