Breakthrough Pain in Cancer Patients: Characteristics, Prevalence, and Treatment

Breakthrough Pain in Cancer Patients: Characteristics, Prevalence, and Treatment

ABSTRACT: "Breakthrough pain" is a common clinical term that has not been conclusively defined or described. Breakthrough pain is a transitory flare of pain experienced when baseline pain has been reduced to a mild or moderate level. Breakthrough pain may be characterized by its relationship to a fixed around-the-clock (ATC) opioid dose, rapid onset and short duration, precipitating events, predictability, pathophysiology (with nociceptive pain being most easily controlled), and etiology. The only prospective study of breakthrough pain conducted to date found a 63% prevalence of breakthrough pain in cancer patients referred to a pain service. Although prevalence figures from other studies vary widely, partly due to the populations chosen, all of the studies verify that breakthrough pain is a serious problem in cancer patients. In fact, several studies have listed incident pain, a subset of breakthrough pain, as a predictor of poor response to analgesic therapy. Breakthrough pain is currently managed with oral or parenteral breakthrough pain medications given in addition to the ATC analgesic regimen. The ATC dosage may also be increased until limited by side effects. Newer agents with a more rapid onset of analgesia and shorter duration of effect may help in the management of breakthrough pain. [ONCOLOGY 12(7):1035-1046, 1998]


Breakthrough pain is currently recognized as an important clinical
phenomenon. It is referred to with increasing frequency in the cancer
pain literature despite a lack of consensus on a formal definition
and despite limited data from controlled research. Contemporary
guidelines for the management of cancer pain uniformly recommend the
provision of supplemental "rescue" or "escape"
doses of short-acting analgesics to manage breakthrough pain, and
most recommend monitoring the frequency of breakthrough pain as a
gauge of the adequacy of treatment with regularly scheduled
analgesics.[1-4] In addition, Bruera and others cite the presence of
incident pain, a specific type of breakthrough pain, as one of the
few indicators that reliably predict a poor response to treatment
with routine pharmacotherapy.[5-8]

Widespread acceptance of empiric treatment and emerging evidence of
the utility of breakthrough pain as a prognostic marker demonstrate
the importance of breakthrough pain as a key component of cancer
pain. Unfortunately, data on breakthrough pain are limited and remain
difficult to interpret, presumably due to variations in how the
phenomenon is defined, assessed, and treated. Although breakthrough
pain occurs in conjunction with baseline pain that is under stable
control, the criteria for what constitutes controlled baseline pain
vary from investigator to investigator. In addition, investigators
differ in their working definitions of breakthrough pain and its
subsets, and a number of studies measure only specific types of
breakthrough pain. All of these factors contribute to the widely
disparate published figures for breakthrough pain prevalence, which
range from 19%[9] to 93%.[10]

The clinical significance of breakthrough pain is also controversial.
Studies intended to evaluate the adequacy of long-acting analgesics
often utilize the incidence of breakthrough pain as a surrogate
outcome measure, and imply that the presence of even modest
breakthrough pain reflects an inappropriately low dosage of regularly
scheduled, around-the-clock (ATC) analgesic.[11-12]Investigators who
are concerned with the identification of factors that predict the
success or failure of pain therapy associate breakthrough pain with
intractability.[5] Still others recommend titration of scheduled and
prn (pro re nata, or as needed) analgesics to balance the adequacy of
overall and breakthrough pain relief against the intensity of
associated side effects and functional impairment.[1,13]

Treatment recommendations for patients with breakthrough pain also
vary considerably. All treatment regimens are empiric, and usually
involve estimating the dose of breakthrough pain medication as a
proportion of the scheduled ATC dosage. Some authorities recommend
the use of prn doses equivalent to a scheduled dose at specific
intervals.[1,14] Others provide breakthrough pain medication doses
every 1 to 2 hours in a dose that is a proportion (usually 5% to 15%)
of the total daily scheduled dose.[15]

Rather than being just an artifact of ATC dosing, breakthrough pain
appears to represent a distinct heterogeneous clinical entity that
warrants careful assessment and an individualized management
approach. With the recognition that breakthrough pain comprises a key
component of chronic cancer pain, it has become increasingly apparent
that there is a critical need for standardization of terminology,
carefully designed epidemiologic studies, and controlled trials of
various treatment approaches.

Temporal Characteristics of Pain

Various schemata for characterizing cancer pain have been advanced
that, when applied, may aid in diagnosis and the determination of
initial and subsequent therapies. These include classifications based
on pain chronicity, intensity, pathophysiology, syndromal
presentation, disease stage, patient characteristics, and temporal
features (Table 1). An appreciation
of the temporal characteristics of pain, including the presence and
nature of breakthrough pain, is a fundamental requisite to a better
understanding of the pain syndrome and the institution of effective treatment.

The temporal characteristics of pain consist of: (1) the presence or
absence of pain at a given moment in time; (2) its intensity or
severity at a given moment in time; and (3) the rate and pattern of
change in intensity or severity over short or long intervals of time
(ie, its tempo). Both acute and chronic pain consist of a series of
related events that can be broadly classified as constant or
intermittent. Chronic pain is usually a relatively constant
phenomenon punctuated by intermittent exacerbations. The constant,
unrelenting component of chronic pain has been variously referred to
as baseline or basal pain. Superimposed intermittent exacerbations of
pain (changes in tempo from baseline) have come to be known
generically as breakthrough pain and have recently become a focus of
intense clinical interest.

The International Association for the Study of Pain (IASP) has
established a taxonomy for painful disorders, which uses an
alphanumeric coding system aimed at assisting clinicians and
investigators in comprehensively classifying painful
disorders.[16,17] This system classified pain along the following
five axes: region, system, temporal characteristics, intensity, and
etiology. Although the temporal classifications suggested by the IASP
may have important implications for researchers, they are expansive
and unwieldy for the clinician managing cancer pain.

Defining Breakthrough Pain

First, breakthrough pain needs to be distinguished from poorly
controlled baseline pain, the pain emergency, and "crescendo
pain." The main feature that distinguishes breakthrough pain
from these other conditions is that, when breakthrough pain occurs,
baseline (basal) pain is, by definition, under relatively stable control.

Although ill-defined and heterogeneous, the pain emergency is best
viewed as an acute condition of mounting pain that occurs either de
novo or in the context of a history of well-controlled pain.[18,19]
In contrast to breakthrough pain, for which the cause is usually
known and symptomatic treatment can thus be implemented, a pain
emergency mandates a diagnostic evaluation aimed at identifying the
etiology of the pain. Pinpointing the cause of the pain may suggest
an appropriate treatment strategy to limit morbidity and even
mortality. Examples of pain emergencies include pain due to bowel
obstruction, pathologic fractures, and epidural spinal cord compression.

Crescendo pain[20] is probably best regarded as a subacute pain
emergency characterized by progressive, unrelenting increases in pain
severity. It is usually described in the context of a history of
stable pain due to cancer and has been reported most often in dying
patients. The presence of crescendo pain implies the need to treat
mounting basal pain, usually with rapidly titrated doses of
parenteral opioids administered by continuous infusion and
supplemental nurse- or patient-administered boluses.

In contrast to breakthrough pain, treatment of crescendo pain is
directed at the entirety of the pain experience, rather than the
exacerbations. Crescendo pain in a dying patient is associated with
special management considerations that may include the use of various
alternate routes, anesthetic or neurosurgical interventions, and even
terminal sedation.[20]

Portenoy and Hagen were the first investigators to propose a
standardized definition of breakthrough pain. They defined
breakthrough pain as a transitory increase in pain to greater than
moderate intensity occurring on a baseline of pain of moderate
intensity or less.[21] Using this definition, Portenoy and Hagen
characterized breakthrough pain in a group of 63 patients. Prior to
this seminal observational study, breakthrough pain had usually been
described only as a secondary outcome measure.[6-10,22,23] Portenoy
and Hagen also identified six characteristics that are relevant to
understanding breakthrough pain: the relationship of breakthrough
pain to a fixed opioid dose, temporal characteristics, precipitating
events, predictability, pathophysiology, and etiology (Table

Relationship to Fixed Opioid Dose

Chronic cancer pain is typically composed of variable components of
basal pain and breakthrough pain and, in this respect, differs from
acute cancer pain syndromes, such as postoperative and
procedure-related pain, which have more predictable, unidimensional
temporal courses.[24] Most guidelines recommend that chronic cancer
pain warranting the use of opioid analgesics be treated with the
concomitant use of two pharmacokinetically distinct preparations of
opioid analgesics. Oncepain is stabilized (usually with short-acting
opioids), baseline pain is typically treated with a relatively
long-acting agent, such as oral controlled-release morphine, oral
controlled-release oxycodone, or transdermal fentanyl

(Duragesic), prescribed on a time-contingent or ATC basis. A
short-acting agent with a relatively rapid onset (eg, immediate-release
morphine, hydromorphone, and oxycodone) is prescribed on a
symptom-contingent or prn basis. In this context, the frequency with
which prn doses are required is used to gauge the need to adjust the
dose of basal analgesic.

End-of-Dose Failure--Breakthrough pain that bears a consistent
relationship to the ATC dosing regimen usually occurs with greater
frequency near the end of a dosing interval and is referred to as
end-of-dose failure. This form of breakthrough pain typically has a
relatively gradual onset and generally lasts longer than pain that is
unrelated to the dosing interval.[25]

The incidence and severity of end-of-dose failure usually correlate
with the adequacy of ATC dosing regimens prescribed for the
management of basal pain. End-of-dose failure is typically more
prevalent and more severe when either basal (ATC) analgesics are
prescribed in inadequate doses or the interval between
administrations is excessive. In contrast to other types of
breakthrough pain, end-of-dose failure is best managed by modifying
the dose or schedule of long-acting ATC opioids.[25]

Other types of breakthrough pain include incident pain
(sometimes referred to as precipitated pain or movement-related pain)
and so-called spontaneous or idiopathic breakthrough pain. Incident
pain has a relatively consistent temporal relationship to specific
events or activities. Breakthrough pain that is unrelated to either
activity or scheduled doses of analgesics is typically referred to as
either spontaneous or idiopathic breakthrough pain. It is worth
noting that McQuay and Jadad advocate an alternate classification
from the one presented here; this system regards breakthrough pain as
a subset of incident pain, rather than the reverse.[26]


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