Management of Pain in The Cancer Patient
Management of Pain in The Cancer Patient
Management of Pain in The Cancer Patient
Author Information
Up to 40% of patients with cancer suffer from pain (1), and up to 80% of
patients with cancer with advanced disease experience moderate to severe
pain (2,3). As many as 25 million people throughout the world die each year
without adequate pain control (4). In patients with progressive cancer, pain
is not a helpful aspect of the disease process. It does not provide useful
diagnostic clues; it leads to suffering and markedly diminishes the patient's
quality of life (5).
Categories of Pain
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Patients with cancer who suffer from pain frequently exhibit signs of
depression and increased anxiety (19). They also exhibit higher depression
and anxiety scores than matched cancer patients not experiencing pain (18).
Suicidal ideation may be present in 7-20% of patients suffering from cancer
pain (20-22). Because signs and symptoms of depression frequently go
unrecognized by primary care physicians (23,24), assessment and
appropriate treatment of affective and anxiety disorders must be included in
any cancer pain management plan. The evaluation and treatment of
psychiatric complications in the patient with cancer recently has been
reviewed elsewhere (22).
Pain may be affected by other behavioral factors (27). For example, the
reaction of significant others to the patient's pain may result in secondary
gain exacerbating pain behavior. Ahles et al reported that more than three-
fourths of cancer patients experiencing pain believed significant others
knew when they were experiencing pain (18). In response, those significant
others offered expressions of concern or aid, and often assumed some of the
patients' responsibilities.
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Patient Assessment
The assessment of pain in cancer patients can be difficult (35). In one study
of cancer pain, nearly twothirds of patients referred for pain consultation
had a previously undiagnosed etiology for their pain (16). The most
frequent source of pain was metastatic neoplasm, but many other causes of
pain were identified. Care should be taken to identify patients who may
benefit from chemotherapy or radiation therapy for palliation and pain
control (36). Examples of causes of pain which are indicators for very
different approaches than simple opioid analgesics are illustrated in Table 2.
Several different assessment methods have been suggested, based on the
etiology, the temporal aspect, or the pathophysiology of the pain.
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Pain Assessment
Etiology of Pain Foley has described pain in the cancer patient based on the
etiology of the pain (1). These syndromes are divided into three major
categories: pain associated with direct tumor involvement, pain associated
with cancer therapy, and pain not associated with cancer or cancer therapy
(Table 3). In a major cancer center, 78% of the pain problems seen in the
inpatient population (1) and 62% of the pain problems seen in the outpatient
population (34) were due to direct tumor involvement. Of the inpatients,
50% experienced pain due to metastatic bone disease, 25% experienced
pain due to nerve compression or infiltration, and 3% experienced pain due
to hollow viscus involvement.
Three percent of inpatient pain problems (1) and 10% of outpatient pain
problems (34) were the result of neither the cancer or cancer therapy.
Causes for such pain included osteoporosis and diabetic neuropathy.
Another study of 100 cancer pain patients (37) reported that more than 20%
of pain experienced by cancer patients was unrelated to the disease or its
treatment. That study led to the recognition of a fourth category: pain
related to chronic disease or debility (Table 4).
Bone pain is the leading specific cause of pain. Up to 85% of patients with
bony tumors or metastases experience severe pain at some time in the
course of their disease. Conversely, less than 10% of patients with
lymphomas or certain leukemias experience severe pain.
Temporal Aspect Cancer pain has also been described according to its
temporal aspect as either acute, chronic, or incidental (41). Acute pain is
characterized by a well-defined temporal onset of limited duration. Chronic
pain is described as pain lasting for more than 3 mo. Incident pain is pain
which occurs on movement, usually due to mechanical changes as a result
of the underlying cancer. An additional term, “breakthrough pain” is also
useful in the description of the cancer pain experience. Breakthrough pain
has been defined as a transitory flare of pain in the setting of chronic pain
managed with opioid drugs (42).
In summary, the evaluation of the patient with cancer pain should be guided
toward identifying the source(s) of the pain. In adults, the most frequent
source of pain is metastatic disease, particularly bone pain. However, other
sources of pain, some of which are not directly the result of cancer, are
frequently present. Diagnosis and treatment of behavioral components of
the pain experience should be part of the care of the patient with cancer
pain. As time progresses, patients often experience changes in their pain,
requiring reevaluation and changes in intervention (34,37).
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Pain Management
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Basic Principles
Large doses of potent opioids can be administered orally. Oral doses often
provide more consistent serum levels than subcutaneous or intramuscular
doses. A large majority of cancer patients can be treated using only the oral
route; however, up to 60% of patients will require additional or alternative
routes of drug delivery during the last 4 wk of life (21,57). In those cases,
intravenous, subcutaneous, epidural, intrathecal, rectal, or other noninvasive
(transmucosal or transdermal) routes should be considered.
Commonly, one type of pain will mask another. When the initial pain is
treated, another pain may appear. Most cancer patients have pain of more
than one etiology. A study of advanced cancer patients revealed that more
than three-fourths of these patients have pain of more than one cause and
more than one-third will experience pain of four or more different etiologies
(37). Each pain must be treated separately as it occurs, and the fact that
multiple pains are common should be explained carefully to the patient.
Continual reassessment of the patient is required to identify the
effectiveness of pain management, to identify and treat adverse side effects,
and because the pain experience itself often changes over time. The
clinician must also ensure that the expertise necessary to provide the
treatment modality is available.
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Analgesic Therapy
Drug therapy which follows the World Health Organization (WHO) cancer
pain relief guidelines (65) or treatment as described by the American Pain
Society (66) is the mainstay of cancer pain management. Drug therapy is
widely available, and is frequently successful if used correctly. Analgesic
therapy according to the WHO guidelines was successful in 71% of patients
suffering from cancer pain during therapy (67) and in at least 76% of
patients suffering from cancer pain at the end of their lives (57). In this
study, only 3% of the patients reported severe or very severe pain following
maximal drug therapy near the time of their death. Parenteral administration
of opioid analgesics is necessary in some patients. Intramuscular
administration is often uncomfortable, inconvenient, and may lead to
inadequate pain control. Intravenous infusion is useful (68,69), especially
when a patient-controlled analgesia (PCA) device is employed (70-72).
Subcutaneous administration can provide good analgesia and is achievable
when small, continuous infusion pumps are used (73-75).
The WHO has described a simple and effective three-step ladder for relief
of cancer pain (Figure 1). The first step is for mild to moderate pain, which
is treated with nonopioid analgesics. These drugs, which include
nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (Table
11), are excellent for treating mild to moderate pain, especially when they
are administered on a time-contingent dosing schedule. In addition to
analgesic effects, NSAIDs also have antipyretic and anti-inflammatory
effects. Acetaminophen, while having analgesic and antipyretic effects,
lacks useful peripheral anti-inflammatory activity.
WHO Analgesic Ladder. Reproduced with permission from the World Health Organization (65).
Analgesics Commonly Used for the Management of Mild to Moderate Cancer Pain
The use of NSAIDs is sometimes associated with numerous side effects,
most notably gastric ulceration and renal damage (76,77). Hepatic, central
nervous system (CNS), and pulmonary side effects rarely occur (78).
NSAIDs may interact with other drugs, such as diuretics, β-blockers, and
some other antihypertensive medications. Careful patient monitoring is
indicated when these drugs are given on a long-term basis (79). These
analgesics also have a ceiling, above which increased doses have no
increased analgesic effect. Patients should be well hydrated. Patients with
true or relative hypovolemia (e.g., those receiving diuretics, congestive
heart failure) are at increased risk for adverse events. Aspirin is normally
avoided in cancer patients with advanced disease because its acetyl moiety
irreversibly impairs platelet adhesiveness. Other NSAIDs, including the
non-acetylated salicylates, cause this effect reversibly and, therefore, are
preferred in many cancer patients.
NSAIDs are especially effective for the management of bone pain and,
therefore, play a major role in the management of cancer pain. The most
common cause of pain in adults and children with active cancer is invasion
of bone by tumor (80) which appears to cause pain by direct involvement of
the bone and activation of local nociceptors and/or by compression of
adjacent nerves, tissues, or vascular structures (80,81).
The second step of the WHO three-step ladder is for moderate to severe
pain and requires the addition of codeine or an analogue of this drug. These
opioids can also be used as alternatives to NSAIDs for the management of
mild to moderate pain if NSAIDs are not tolerated or are contraindicated.
Codeine, oxycodone, and hydrocodone are the most frequently used opioids
in this group. These drugs often are given together with to a nonopioid
analgesic, because the combination results in potentiation due to the fact
that opioids act centrally and NSAIDs act primarily in the periphery (82).
The third step of the WHO ladder is for the management of severe pain.
Codeine or a congener is replaced with a more effective opioid, usually
morphine. Morphine (83), hydromorphone, and methadone (84) are
frequently used potent opioids. The dosage of the opioid is individualized
for each patient (83) and often requires adjustment over time. Occasionally,
the cancer patient may require massive doses of opioids for adequate pain
management (21,85,86). While the analgesic potency varies among opioids
(Table 12), effective analgesia can be obtained with most of the drugs in
this class. The selection of an opioid for a particular patient is often made
on the basis of the possible adverse side effects with a particular drug in that
patient, drug cost and availability, and the prescribing physician's
experience.
Opioids depress respiration and must be used with caution in patients with
impaired respiratory capability. However, pain also suppresses breathing in
many patients, especially those with chest disease or injury. Too often,
opioids are wrongly withheld or incorrectly dosed in patients with impaired
respiratory capability. A study of patients with lung cancer who received
aggressive opioid analgesia for pain relief revealed that the drugs did not
adversely affect respiratory function as determined by analysis of arterial
blood gases (90).
Fentanyl has been incorporated into a transdermal delivery system and has
been released for use in the management of chronic pain requiring opioid
administration (TTS-fentanyl) (92,93). TTS-fentanyl is designed to deliver
fentanyl at a constant rate of 25, 50, 75, or 100 μg/h. Plasma concentrations
of fentanyl increase slowly with the TTS-fentanyl system and peak only
after about 15 h. The fentanyl levels remain level, then decrease slowly
after removal of the patch, with an apparent half-life of 21 h (Figure 2) (94).
This system may be useful in selected cancer pain patients in whom the oral
tract is no longer available for opioid delivery, or who experience adverse
side effects to oral morphine or methadone. This dosage form should not be
used to titrate patients' doses due to the long time needed to achieve steady
state serum levels. Fentanyl is much more expensive than oral morphine or
methadone and should be used only when more conventional alternatives
have failed. Other noninvasive drug delivery systems, such as iontophoresis
of morphine (95) and oral transmucosal fentanyl citrate (OTFC) (96-98),
are being investigated. They may have a role in the management of cancer
pain, but are not currently available for clinical use.
Mean serum concentrations of fentanyl in patients who received fentanyl transdermally, preceded by a 300-μg loading dose at time zero (error bar ± SD). Reproduced with
permission from Holley and van Steenis (94).
Adjuvant Drugs Adjuvant drugs are suggested for consideration at each step
of the WHO three-step analgesic ladder. Adjuvant drugs are those drugs
which enhance the effects of analgesics, have independent analgesic activity
in certain pain syndromes, or lessen other symptoms which exacerbate pain.
Adjuvants include the tricyclic antidepressants, anticonvulsants, and
steroids.
Steroids have several benefits to the cancer patient. They can lower pain
perception, have a sparing effect on opioid dose, improve mood, increase
appetite, and lead to weight gain. In the patient with advanced disease,
steroids can improve quality of life (112). In addition, steroids are part of
the routine management of patients suffering from spinal cord compromise
secondary to tumor because steroids reduce edema in the tumor and nervous
tissue (81). Steroids alone are effective in the management of bone pain
caused by metastatic breast and prostate cancer. Many of these effects are
seen at relatively low doses, e.g., 5-10 mg of prednisone each morning.
Relatively low mineralocorticoid drugs, such as prednisone or
dexamethasone, should be used to lessen the risk of exacerbating edema
and water-electrolyte disturbances associated with the underlying disease.
Long-term use of steroids can lead to weight gain, Cushing's syndrome,
proximal myopathy, and rarely psychosis. In addition, NSAIDs should be
used with extreme caution or not at all in patients receiving steroids, as the
combination increases the risk of gastric ulceration and gastrointestinal
bleeding.
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Until recently, the duration of spinal opioid administration has been limited
(116). Catheters designed for short-term use frequently dislodge, occlude,
or break if left in place for more than several days. The development of new
catheter materials and placement techniques has allowed delivery of spinal
opioids for weeks to months (117-119). This can be accomplished by the
placement of long-term, subcutaneously tunneled, exteriorized catheters, or
by the use of implantable drug delivery systems. The implantable systems
can be either intrathecal (120-122) or epidural (48) and feature either a drug
reservoir (123) or an implanted infusion device (117). More recent models
of the implanted infusion devices allow for external reprogramming.
Complications often occur with all the long-term spinal opioid delivery
systems, which may limit their usefulness (127). These include superficial
and deep infection, catheter malfunction, and pain on injection (128,129).
There is an infection rate of 5% with a longterm externalized, tunneled
catheter (128) which can become occluded or dislodged and require
replacement. In addition, up to 12% of patients develop pain on injection,
possibly due to formation of a fibrous sheath around the catheter tip (130).
Similar complications can occur with implanted devices. The use of a Port-
A-Cath implanted epidural access system caused 6.7% of the patients to
experience a superficial or deep infection, and 16% of the catheters
migrated, leaked, or became occluded (Table 13).
System-related Complications
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Neurolytic Procedures
Neurolytic celiac plexus block has been used to treat pain originating from
the abdominal viscera (141,142). Blockade of the celiac plexus is often
effective in the management of pancreatic cancer pain, as well as for other
cancer pain originating in this area of the body (143-145). The block can be
completed using alcohol or phenol, and may be successful 80% of the time.
Analgesia usually lasts for more than a month and may last 6 months or
longer. The block is associated with many complications, but these are
infrequent or easily managed. Although there are several reports advocating
celiac plexus block, others have criticized these studies and question its role
(146).
Epidural neurolytic nerve blocks have been used for the management of
thoracic and cervical cancer pain (150). While the technique is fairly
simple, it can cause a large sensory deficit. In addition, motor block and
loss of bladder and rectal sphincter function can occur. Although motor
function usually resolves over time, it can be long lasting.
Dorsal rhizotomy involves the interruption of the sensory nerve root. It can
be completed as an open surgical procedure or by the use of a neurolytic
agent (160,161). Dorsal rhizotomy is used when pain is localized to a
specific dermatomal level, and may be useful in the treatment of pain
involving the chest wall (162). Some authors have advocated dorsal
rhizotomy for perineal pain (160,163). Unfortunately, it has limited
usefulness in the treatment of pain involving the upper extremity.
Rhizotomy of the trigeminal nerve, glossopharyngeal nerve, and vagus
nerve also have been attempted for treatment of pain involving the head and
neck with variable results (164). Other neurosurgical procedures, such as
radiofrequency cingulotomy, have been described recently for the treatment
of intractable cancer pain (119,165). As with cordotomy, the experience
with the use of rhizotomy and cingulotomy is limited and not widely
available.
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Summary
The pain experience of the cancer patient is the result of many factors,
including nociceptive sources, specific pain syndromes, and behavioral
contributions. Careful evaluation of the patient is necessary to identify the
contributors to the patient's pain experience and to select treatment
modalities which address the underlying causes. For patients who are
experiencing poorly controlled pain as a result of cancer, therapy often
includes multiple management strategies involving more than one
discipline. Therefore, an interdisciplinary approach may be more useful for
pain management (15). Disciplines and specialties involved in such care
commonly include anesthesiologists, oncologists, psychiatrists,
psychologists, physical therapists, pharmacists, nurses, and social workers.
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