Cancer pain is experienced by 30% to 45% of
patients at the time of diagnosis and by about 75% of patients
with advanced disease. Good pain control can be achieved in most
patients with cancer pain but commonly requires the use of
rescue or supplemental doses of analgesic. Standard
practice in palliative care is to prescribe both scheduled doses of
an analgesic (around-the-clock dosing) for persistent pain and
supplemental doses as needed for breakthrough pain.
Defined as a transitory exacerbation of pain that occurs on a
background of otherwise stable persistent pain, breakthrough
pain has been associated with a reduced likelihood for adequate pain
control in some groups of cancer patients. Breakthrough pains
characteristically have a rapid onset and severe intensity but brief
duration (range, 1 to 240 minutes; median, 30 minutes). Pain of such
an intense severity but short duration is particularly difficult to
treat because currently available oral agents administered at the
onset of a breakthrough pain episode may require 30 to 45 minutes to
be absorbed and produce an analgesic effect.[6-9] Because
breakthrough pain, like other types of cancer pain, may limit patient
mobility, adversely affect a patients mood, and inhibit social
interactions, skill in managing breakthrough pain may
significantly affect a patients quality of life.
Breakthrough pain may be caused by somatic, visceral, or neuropathic
pathophysiology, and it is most often related to the same mechanism
that causes the persistent pain. By definition, breakthrough pain is
of moderate or severe intensity. Although the onset of breakthrough
pain is often paroxysmal (peaking in intensity within 3 minutes), it
may develop gradually. Like persistent cancer pain, breakthrough pain
may be related directly to the location of the neoplasm, treatment
effects, or other etiologies.
Breakthrough pain may be classified according to precipitating
events. Breakthrough pain related to movement is generally termed
incident pain. Incident pain may be caused by volitional movements,
such as walking or sitting, or nonvolitional movements, such as bowel
or ureter distention. Breakthrough pain that is not linked to
scheduled analgesic dosing and that cannot be linked to bodily
movement or function is called spontaneous or idiopathic breakthrough
pain. Pain exacerbations that typically occur at the end of the
dosing interval of an around-the-clock opioid are termed end-of-dose failures.
Breakthrough pain is managed primarily with supplemental opioid
analgesics, but multiple modalities may be used. One study that asked
patients to report palliative measures that lessened breakthrough
pain listed numerous measures, in addition to the use of supplemental
analgesic doses; these included a change in position or movement and
suppression of a pain-inducing movement (eg, cough).
Because breakthrough pain (like persistent pain) is often related to
neoplastic growth, primary treatment measures, including
antineoplastic therapy, should be considered. Increasing the
around-the-clock medication dosage may also be considered but may be
associated with unacceptable side effects. The goals of cancer pain
therapy are to find the right dose of around-the-clock medications to
control persistent pain and the right dose of supplemental medication
to relieve breakthrough pain. Pharmacologic therapy combined with
non-pharmacologic measures should control pain in most patients.
In the past, many physicians considered palliative care only after
all active antineoplastic treatments had failed. Failure to
attempt to relieve pain and other symptoms, however, is unacceptable
at any phase of the cancer treatment process. Recent issues (such as
assisted suicide requested by patients suffering pain related to
terminal illness) have underscored the importance of pain relief to
patients. Appropriate analgesia should therefore be used alone or
in combination with active antineoplastic therapy as part of standard treatment.
This discussion of primary therapies does not mean to imply that
palliative care should be instituted only after primary therapy has
been terminated. Indeed, analgesics should be offered as soon as they
are required, since patients who are in less pain experience
improvements in sleep, mental attitude, appetite, and general quality
Primary therapy and pain management should be used together, although
the need to increase pain management strategies typically arises when
active neoplastic therapy becomes less effective, often during the
later stages of disease. Sometimes, however, a primary neoplastic
therapy may not be curative but may substantially alleviate pain.
Thus, irradiation of a metastatic tumor on or near nerves or
weight-bearing bones could potentially relieve a patients pain.
Chemotherapy used to treat particularly painful conditions, such as
pancreatic or prostate cancer, may also lessen pain. For this reason,
agents such as gemcitabine (Gemzar) and mitoxantrone (Novantrone)
have been approved for palliative care, even though they are
traditionally considered to be antineoplastic agents.[13,14]
Primary therapies need not treat the neoplasm directly. Breakthrough
pain due to coughing, for instance, may be managed with an
antitussive agent. Similarly, stool softeners may lessen pain
associated with defecation. Movement-related pain may sometimes be
ameliorated by orthotic devices. Finally, surgical means of pain
relief, such as denervation or joint replacement, are generally
reserved for highly specific situations or severe, intractable pain.
Increase in Dosage of Around-the-Clock Analgesics
Pain cannot always be managed by removing its direct cause. Most
primary interventions are associated with risks, complications, and
side effects that may make strict analgesic treatment of pain preferable.
Traditionally, frequent episodes of breakthrough pain have been
treated with increased dosages of regularly scheduled analgesics.
This practice developed, in part, because of the appropriate goal of
trying to prevent as much pain as possible. In addition, due to their
pharmacokinetics, the available oral analgesics often take longer (30
to 45 minutes) to provide relief than is acceptable to patients.
Increased dosages of around-the-clock analgesia may mask some of the
less severe exacerbations of pain.
Increasing the dosage of around-the-clock medications, however,
increases the opioid levels present in the blood at all times,
thereby increasing the likelihood of opioid side effects. In patients
with few side effects from opioid therapy, increasing the
around-the-clock dosage may not be problematic. In patients with
constipation, sedation, confusion, or similar side effects, however,
increasing the around-the-clock dosage may disturb the balance
between analgesic effectiveness and side effects. Thus, the
likelihood of increasing analgesic side effects should be weighed
against the need for around-the-clock analgesia before
around-the-clock dosage is altered.
Supplemental analgesic agents, sometimes referred to as
rescue analgesics, are crucially important in the
management of breakthrough pain. Historically, supplemental
analgesics have been dosed as a percentage of the around-the-clock
analgesic dose. The rule of thumb has been to use a short-acting
formulation of the long-acting around-the-clock analgesic, whenever
possible; in general, the supplemental dose has been 5% to 15% of the
daily around-the-clock dose, administered every 1 to 2 hours.
As more analgesic agents have been used more widely to treat cancer
pain, it has become acceptable to prescribe different opioids for
around-the-clock and breakthrough pain, provided that the combination
does not unacceptably increase side effects. Indeed, around-the-clock
analgesics, such as transdermal fentanyl (Duragesic) and methadone,
have commonly been combined with another opioid for breakthrough
pain. (Note, however, that methadone is not commonly considered for
initial therapy of cancer pain due to its long and unpredictable
half-life.) Like the around-the-clock medication, the supplemental
analgesic should be titrated to manage persistent pain and to provide
adequate analgesia with acceptable side effects.
In theory, the use of supplemental analgesic agents in combination
with around-the-clock medications should provide more effective
analgesia with fewer side effects than long-term scheduled analgesics
used alone because higher levels of analgesic are present in the
bloodstream only when pain relief is needed (Figure
1a). In reality, however, the delay between the administration
of supplemental analgesics and their absorption and the achievement
of pain relief can leave a patient suffering from excruciating pain
during the interim (Figure 1b).
Thus, many physicians treat breakthrough pain prophylactically,
maintaining higher dosages of around-the-clock analgesic at all
times. In some patients, however, this strategy may result in
unbearable side effects, such as sedation, nausea, or constipation (Figure
When oral supplemental analgesics are used, the patient must often be
asked to accept a balance between the side effects associated with
long-acting opioids and the pain experienced between the time a
breakthrough pain begins and the time when analgesics take effect.
New supplemental analgesics that are rapidly absorbed via novel
routes of administration may allow clinicians to approach the ideal
of breakthrough pain relief by providing active drug that circulates
systemically more quickly to bring relief as soon as the pain occurs.
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