As indicated in this review by Patt and Ellison, the literature
pertaining to the association between transitory acute pains and
chronic cancer-related pain is limited and plagued by nomenclatural
problems. Nonetheless, the clinical relevance of these so-called
breakthrough pains is apparent to those who treat cancer patients.
Moreover, the existing empiric evidence is sufficient to conclude
that the phenomenon is prevalent, highly variable, and likely to
complicate the outcome of routine opioid-based pharmacotherapy.
Further research and education into the nature and treatment of
breakthrough pain will occur as novel therapeutic approaches become
commercially available in the near future.
Patt and Ellisons comprehensive review describes our current
understanding of breakthrough pain and the consensus regarding its
management. Several issues deserve special emphasis.
Definition of Breakthrough Pain--A Paradox
The clinical relevance of breakthrough pain is suggested by the
widespread acceptance of "rescue" dosing as a part of
routine analgesic therapy. Techniques for the use of this
supplemental treatment during fixed-schedule opioid administration
evolved in the complete absence of randomized, controlled trials
supporting the approach.
The acceptance of rescue dosing by clinicians and patients alike
indicates that most cancer patients readily understand the difference
between baseline pain and breakthrough pain, and that physicians and
patients can translate this understanding into a therapeutic approach
that appears to address a substantial clinical problem. Thus, the
definition of breakthrough pain is characterized by a paradox:
Although problematic to investigators who seek to characterize and
measure this heterogeneous subtype of pain in the medically ill, the
nature of the phenomenon appears to be intuitively obvious to most
patients and physicians.
Development of a Valid Measurement Approach
Systematic efforts to explore the characteristics, impact, and
treatment of breakthrough pain require the development of a valid
measurement approach. One assessment approach has been proposed for
use in epidemiologic surveys. Although this approach has not been
independently validated, it has yielded informative data in two
survey[reference 2 and Portenoy RK et al, unpublished data] and could
be considered a starting point for the development of better systems.
This assessment uses standardized questions to categorize patients
into three groups:
Those with uncontrolled baseline pain
Those with controlled baseline pain and no breakthrough pain
Those with both controlled baseline pain and breakthrough pain
The first question distinguishes patients with chronic baseline pain
from those with either no clinically significant pain or pain that is
recurrent. Patients are asked whether pain has been present for more
than half the time that they were awake during the prior week, or
whether they used a fixed-schedule opioid regimen on more than half
the days during that period. Patients who answer affirmatively are
considered to have chronic baseline pain.
A second question distinguishes "controlled" from
"uncontrolled" baseline pain. Using a four-point
verbalrating scale, patients are asked to characterize the usual
intensity of the baseline pain, ie, the intensity experienced for
more than half the time that pain is present. The responses range
from "absent," if the analgesic regimen is highly
effective, to "usually severe." Patients whose baseline
pain is usually absent, mild, or moderate are considered to have
controlled baseline pain.
Patients who have controlled, chronic baseline pain may be asked
whether they have experienced one or more episodes of severe or
excruciating pain during the past day. An affirmative response to
this question distinguishes patients with both controlled baseline
pain and breakthrough pain, and allows follow-up questions that
specifically focus on the characteristics and impact of breakthrough
pains. As described by Patt and Ellison, the characteristics that
appear to be important in clinical practice include the types of
breakthrough pain, their temporal features (frequency, onset, and
duration), etiology and inferred pathophysiology, precipitating
events (including the relationship to the fixed opioid dose),
predictability, impact, and factors that reduce either frequency or
intensity (including both prescribed therapies and maneuvers
discovered by the patient).
Breakthrough Pain, Opioid Responsiveness, and Outcomes
Patt and Ellison describe the results of surveys that suggest an
association between the experience of breakthrough pain and
relatively poor opioid responsiveness. Breakthrough pain could be an
indicator of a more severe pain syndrome overall, which is
characterized by a reduced response of the baseline pain to optimally
administered opioid therapy. Alternatively, only the breakthrough
pain itself may be difficult to relieve and thereby reduce the
likelihood of a favorable response. Regardless, clinicians must
recognize that the presence of breakthrough pain may indicate a
challenging pain syndrome and require special attention.
Recent data also suggest that the presence of breakthrough pain may
be associated with adverse outcomes related to both physical and
psychosocial functioning. A survey of 178 cancer patients noted that
patients with breakthrough pains reported significantly greater
impairment on validated measures of pain-related functional
interference and mood than those without these pains.[Portenoy RK et
al, unpublished data] Although additional studies are needed to
clarify this association, the data underscore the importance of
breakthrough pain as an issue in clinical practice.
Available Therapeutic Approaches
Patt and Ellison describe the many therapeutic approaches available
for breakthrough pain. They appropriately emphasize the importance of
the assessment in selecting treatments. In some cases, breakthrough
pain can be ameliorated by treatment of an underlying cause. This
treatment can be directed against a structural problem (such as
radiotherapy to a bone metastasis) or a physiologic process (such as
the effective use of an antitussive to treat cough-induced
Patt and Ellison also correctly note that some patients appear to
experience fewer or less intense breakthrough pains when the dose of
the fixed-schedule opioid regimen is increased. There have been no
studies of this approach, but its use is recommended by its
simplicity. To help manage breakthrough pain, the dose of the
fixed-schedule opioid regimen should be gradually increased until the
patient begins to experience treatment-limiting side effects. These
side effects, which often occur in the periods between breakthrough
pains, define the upper limit of the therapeutic window.
New Treatments in Development
Members of the pharmaceutical industry are now engaged in new product
development focused on the treatment of breakthrough pain. To date,
oral transmucosal fentanyl citrate (Actiq) is the only formulation to
be studied systematically. Its efficacy has now been demonstrated in
the first randomized, controlled study of the rescue dose. Other
controlled trials of this formulation have been completed and further
demonstrate the feasibility of such studies. Although the
investigation of transitory pains in medically ill outpatients
already receiving opioid drugs on a fixed-scheduled basis is clearly
challenging, innovative methods can be developed to obtain valid
information about the safety and efficacy of novel therapies.
The future will undoubtedly see the development of a variety of new
pharmacologic approaches to treat breakthrough pain. Hopefully,
studies of the routine approaches described by Patt and Ellison will
also be performed and will provide a better scientific foundation for
current guidelines advocating the use of short-acting oral or
parenteral opioid rescue doses. Combined with systematically
collected epidemiologic data, these studies will further improve the
recognition of breakthrough pain as an important clinical phenomenon
and provide clinicians with a better range of therapeutic approaches
with which to manage the problem.
1. Jacox A, Carr DB, Payne R, et al: Management of Cancer Pain. AHCPR
publication no. 94-0592, Clinical Practice Guideline no. 9.
Rockville, Maryland, US Department of Health and Human Services,
Public Health Service, March 1994.
2. Portenoy RK, Hagen NA: Breakthrough pain: Definition, prevalence,
and characteristics. Pain 41:273-281, 1990.
3. Farrar JT, Cleary J, Rauck R, et al: Oral transmucosal fentanyl
citrate: A randomized, double-blind, placebo-controlled trial for the
treatment of breakthrough pain in cancer patients.J Natl Cancer Inst