Temporal Characteristics: Onset and Duration
Breakthrough pain can be characterized by its specific temporal
features; these include its rapidity of onset, duration, and
frequency. The onset of breakthrough pain has been classified as
sudden or paroxysmal vs gradual. Sudden or paroxysmal episodes have
been arbitrarily defined as those arising within 3 minutes, while
gradual-onset breakthrough pain establishes itself more slowly.With
regard to duration, an arbitrary value of 20 minutes has been
suggested as the cut-off for classifying an episode of breakthrough
pain as brief or sustained. Exacerbations of pain that occur very
frequently and/or for sustained intervals are probably best regarded
as representing a recrudescence of basal pain, rather than
breakthrough pain. Studies to date demonstrate considerable
variability in the frequency of breakthrough pain, supporting the
notion that breakthrough pain is a highly heterogeneous phenomenon.
As noted, breakthrough pain may be either spontaneous or precipitated
by a recognizable event (incident pain or precipitated pain).
Precipitated pain may be volitional (ie, induced by an action subject
to some control, such as movement, swallowing, and coughing) or
nonvolitional (ie, caused by events that are subject to less control,
such as flatulence, myoclonic jerking, and anxiety). Breakthrough
pain associated with volitional activity is commonly referred to as
The concepts of predictable pain and precipitated pain are closely
related to that of incident pain, although these terms are not
synonymous. Predictable pain refers to the fact that, especially with
coaching, patients often are able to correlate the occurrence of
breakthrough pain with discrete actions (ie, precipitating events).
Precipitated pains are usually, but not always, predictable. For
example, pain related to involuntary movement in patients with
myoclonus is precipitated but not always predictable. Seemingly
spontaneous pain is sometimes predictable, especially when associated
with environmental cues, such as the presence of a family member.
When trained to appreciate environmental cues (eg, stress), patients
often can be taught to predict episodes of breakthrough pain with
A pathophysiologic classification of pain that distinguishes among
somatic nociceptive, visceral nociceptive, and neuropathic pain is
widely accepted and is clinically relevant to breakthrough pain.
Somatic and Visceral Nociceptive Pain--Pain of somatic
nociceptive origin emanates from injury to nonneurologic, nonvisceral
connective tissues, such as muscle, bone, skin, ligaments, and
joints. It is characteristically described by patients in familiar
terms that are culturally linked to pain, such as sharp, stabbing,
dull, and achy. Prototypical examples of somatic nociceptive pain
include soft-tissue trauma, postoperative pain, bone metastases, and
Pain of visceral nociceptive origin emanates from injury to hollow or
solid viscera, is often diffuse, and is characteristically described
as vague, dull, dragging, or pressure-like. Examples include labor
pain, bowel obstruction, and pain due to liver capsule distention.
Somatic and visceral nociceptive pain originate with activation of
peripheral A-delta and C nociceptors by noxious mechanical, chemical,
or thermal stimuli. Impulses are conveyed along classically described
neuroanatomic pain-conducting pathways that include the dorsal horn
of the spinal cord, contralateral spinothalamic tract, thalamus, and
subcortical and cortical structures. Impulses are modulated by both
biochemical and cognitive mechanisms. Somatic or visceral nociceptive
pain typically responds robustly and in a relatively linear manner to
treatment with opioid analgesics.
Neuropathic pain follows obvious or subclinical injury to
parts of the peripheral or central nervous system. It is often, but
not invariably, associated with abnormal neurologic findings, ranging
from reproducible sensory or motor deficits to subjectively abnormal
(dysesthetic) sensations. These abnormal sensations may include
paresthesias, hyperalgesia, hyperpathia, allodynia, and hyperesthesia.[17,28,29]
In contrast to nociceptive pain, neuropathic pain is often described
as a bizarre or foreign experience for which there is no familiar
frame of reference. It is typically described in terms that are not
culturally linked to pain, such as tingling, numb, burning,
lancinating, or shock-like. Prototypical conditions associated with
neuropathic pain include diabetic neuropathy, herpes zoster,brachial
plexopathy, spinal cord injury, peripheral nerve compression, and amputation.
The mechanisms responsible for the development and maintenance of
neuropathic pain are less clearly understood than those that
contribute to nociceptive pain. They include the propagation of
abnormal sensations to the central nervous system, plasticity, and
wind-up phenomena. Plasticity is the nervous systems potential
ability to adapt (functionally and structurally) to stimuli,
including injury. Wind-up phenomena occur when a barrage of
peripheral stimuli acts to facilitate firing of the spinal cords
wide dynamic range (WDR) neurons, which, in turn, contributes to hyperalgesia.
Neuropathic pain may be less responsive to opioids than nociceptive
pain, and, in contrast to nociceptive syndromes, is more likely to
respond favorably to treatment with adjuvant analgesics (eg,
antidepressants, anticonvulsants, and oral local anesthetics).
Neuropathic pain has been further categorized as deafferentation or
central pain, depending on whether the causative injury involves the
peripheral or central nervous system, respectively. This distinction
has fallen out of favor, however, based on the perception that it has
few practical therapeutic implications.
The etiology of breakthrough pain in cancer patients may be related
directly to tumor progression (eg, bone metastasis, nerve
compression), cancer treatment (eg, postmastectomy pain,
osteoradionecrosis, polyneuropathy after chemotherapy), or disorders
unrelated to the cancer (eg, discogenic low back pain, arthritis). As
Foley has pointed out, these contextual distinctions influence
the meaning of pain to the patient. As a result, the degree of
suffering experienced and the patients ability to cope vary
considerably depending, respectively, on whether the pain is regarded
as life-threatening, a barrier to rehabilitation, or simply a chronic annoyance.
Breakthrough pain has only recently been recognized as a distinct
clinical entity. Relatively few studies describe this phenomenon in
detail, and, thus, its prevalence is difficult to ascertain. Although
numerous researchers refer to the number of patients experiencing
breakthrough pain (Table 2) as an
incidental finding in the course of studies evaluating other aspects
of cancer pain,[22,33,34] Portenoy and Hagen are the only
investigators who have conducted a prospective evaluation of
breakthrough pain in cancer patients. Breakthrough pain has not been
formally evaluated in populations of noncancer patients.
Studies Explicitly Evaluating Breakthrough Pain
To date, Portenoy and Hagens study provides the most
careful characterization of breakthrough pain (Table
3). These investigators evaluated all adult inpatients referred
to a pain service at a comprehensive cancer center over a 3-month
period. Of this cadre of 90 patients, 70 met the investigators
criteria for stable analgesic dosing (dose increases of no more than
20% per day for 48 hours), 63 of whom were determined to have
well-controlled baseline pain (defined as pain of moderate intensity
or less). Of these 63 patients, 41 (63%) met the studys
criteria for the presence of breakthrough pain (temporary flares of
severe or excruciating pain) and were surveyed regarding the nature
of the breakthrough pain that they experienced over the prior 24 hours.
Of the 51 breakthrough pain episodes, 55% were identified as incident
pain and 29% as end-of-dose failure. End-of-dose failure and incident
pain (mixed breakthrough pain) were concomitantly present in 43% of
pain episodes, and 45% of episodes were idiopathic in nature.
Three-quarters of breakthrough pain episodes appeared to be directly
related to tumor activity, with most of the remaining episodes
presumed to be due to antitumor therapy. Breakthrough pain appeared
to be mediated by a variety of underlying mechanisms, and almost all
of the episodes occurred in the same location as patients
The median number of breakthrough pains over a 24-hour period was 4
(range, 1 to 3,600 pains), and about one-fourth of patients
identified more than one distinct type of breakthrough pain.
Breakthrough pain arose rapidly (< 3 minutes) in 43% of patients
and more gradually (> 3 minutes) in the remainder. The median
duration of breakthrough pain was 30 minutes, and 41% of the episodes
were both of rapid onset and brief duration. Data on duration are
presumably influenced by the routine in-hospital use of breakthrough
pain medications; the 30-minute median duration observed is
consistent with the usual latency-to-effect for standard analgesics.
Bruera and colleagues described their observations on the
incidence and nature of incident pain in the context of an open trial
on the use of methylphenidate to counter opioid-mediated sedation. In
contrast to the study of Portenoy and Hagen, this reports
scope was limited to the subset of patients with incident-type
breakthrough pain who had already therapeutically achieved
"well-controlled pain." Since its focus was the evaluation
of a therapeutic intervention, the study by Bruera et al provided
fewer details on pain characteristics.
Brueras group screened 118 consecutive patients admitted to an
inpatient palliative care unit, all of whom had advanced cancer and
pain. They identified 23 patients (19%) with "severe incident
pain," of whom 14 were ultimately evaluable. The authors defined
incident pain as spontaneous or provoked "severe" acute
exacerbations of pain occurring against a background of
"good" opioid-mediated pain control. All patients were
receiving oral or subcutaneous (SC) morphine or hydromorphone in
fixed ATC doses.
Incident pain appeared to be due to bone metastases in 12 (86%) of 14
patients, and was presumed to be related to chest wall invasion and
inguinal adenopathy in the remaining 2 patients. Movement appeared to
be responsible for provoking pain in all cases: Pain was precipitated
by sitting in 2 patients, standing and walking in 2 others, and
unspecified movement in the remaining 10 patients (71%).
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