PRACTICE GUIDELINE

MANAGEMENT OF BREAKTHROUGH CANCER PAIN, Daeninck et al.

Canadian recommendations for the

management of breakthrough cancer pain
P. Daeninck md,* B. Gagnon md, R. Gallagher md, J.D. Henderson md, Y. Shir md,||
C. Zimmermann md phd,# and B. Lapointe md**

ABSTRACT
Breakthrough cancer pain (btcp) represents an important element in the spectrum of cancer pain management.
Because most btcp episodes peak in intensity within a few minutes, speed of medication onset is crucial for proper
control. In Canada, several current provincial guidelines for the management of cancer pain include a brief discussion
about the treatment of btcp; however, there are no uniform national recommendations for the management of btcp.
That lack, accompanied by unequal access to pain medication across the country, contributes to both regional and
provincial variability in the management of btcp.
Currently, immediate-release oral opioids are the treatment of choice for btcp. This approach might not always
offer optimal speed for onset of action and duration to match the rapid nature of an episode of btcp. Novel transmucosal fentanyl formulations might be more appropriate for some types of btcp, but limited access to such drugs hinders
their use. In addition, the recognition of btcp and its proper assessment, which are crucial steps toward appropriate
treatment selection, remain challenging for many health care professionals.
To facilitate appropriate management of btcp, a group of prominent Canadian specialists in palliative care,
oncology, and anesthesiology convened to develop a set of recommendations and suggestions to assist Canadian
health care providers in the treatment of btcp and the alleviation of the suffering and discomfort experienced by
adult cancer patients.

Key Words Breakthrough cancer pain

Curr Oncol. 2016 Apr;23(2):96-108

INTRODUCTION
Despite recent advances in diagnosis, assessment, and
treatment, breakthrough cancer pain (btcp) continues to
present a significant challenge for patients, their caregivers,
and health care professionals. Furthermore, because of a
lack of uniform Canadian guidelines and recommendations about the management of btcp, significant provincial,
regional, and inter-institutional variations in therapeutic
approaches persist. To streamline the management of
btcp across the country, a group of prominent Canadian
clinicians involved in the care of cancer pain, including
individuals with expertise in anesthesiology, oncology, and
palliative care, were gathered by the two co-chairs of the
expert panel. The members of the expert panel are involved
clinically and academically, particularly in the teaching of
pain management. Each of the clinicians has participated
in research, and all have published in their respective fields.
Based on relevant literature, recent evidence, anecdotal

www.current-oncology.com

reports, and personal experience, the experts developed a

set of recommendations and suggestions, with the objective
of guiding Canadian clinicians in the treatment of btcp in
daily practice. The main goal was to assist Canadian health
care providers and policymakers in the decision-making
process and thereby to improve outcomes and quality of
life for patients with cancer.

METHODS
A search of the English-language literature in PubMed
and the Cochrane Library used the terms breakthrough
cancer pain or cancer pain to identify relevant studies
published from January 2008 to December 2014. However,
the literature search was not limited to that period, because
it was followed by a manual search of references cited in
selected papers published in peer-reviewed journals.
Meta-analyses, systematic reviews, and randomized
clinical trials were the preferred sources.

Correspondence to: Paul Daeninck, CancerCare Manitoba, 409 Tache Avenue, Winnipeg, Manitoba R2H 2A6.
E-mail: pdaeninck@cancercare.mb.ca n DOI: http://dx.doi.org/10.3747/co.23.2865

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MANAGEMENT OF BREAKTHROUGH CANCER PAIN, Daeninck et al.

The search was refined according to specific topics

determined during a consultation process with the expert
panel members. Subsequently, each member of the expert
panel was assigned a specific topic for which that member
reviewed selected references to ensure relevance and
acceptable methodologic quality. The key findings were
presented and discussed during a consensus meeting that
took place 24January 2015 in Montreal, Quebec. During the
meeting, the experts reviewed the evidence and formulated
recommendations, taking into consideration the benefits,
risks, and side effects of various interventions. Consensus
was reached by discussion during the meeting. The resulting manuscript was further revised by the entire group.
Revision comments were discussed by the group, agreed
upon, and integrated.
The guidelines highlight key points from the data in
three ways:

onset, with escalation to maximum intensity in as little

as 1 minute 37. The frequency of the pain episodes can
vary from a single time to several times daily or weekly7,8.
However, frequent occurrence of btcp can be indicative
of uncontrolled baseline pain and a need to revisit the
therapeutic approach for background pain.
Although some authors also consider end-of-dose pain
as a subtype of btcp, this type of pain, caused by declining
analgesic levels, is a consequence of poorly controlled
background pain and does not represent true btcp4. Rather,
it indicates that the around-the-clock analgesic approach
should be re-assessed.
Breakthrough cancer pain can be divided into two
categories: incident (predictable) and spontaneous (idiopathic, unpredictable) pain (Figure2). Incident btcp is
related to a specific identifiable cause and can be subclassified into one of three categories9 :

Consensus points are evidence-based statements

concerning the current understanding of btcp diagnosis and management.
Education points are identified unmet needs and
challenges for which additional learning activities
might be required.
The 8 general recommendations that were formulated
can be used to guide clinical practice and management
of btcp in Canada.

The recommendations presented here are not a replacement for clinical judgment and cannot be used as
a legal resource because they do not provide individual
guidance in all situations. In fact, when considering therapeutic approaches for cancer pain, health care providers
must consider the needs, preferences, values, financial
situation, and personal context for each individual patient.

BTcP: COMMON CHARACTERISTICS

AND CONTRIBUTING FACTORS
Pain is a common occurrence in patients with cancer and
especially in those with advanced disease1. Cancer pain
is multifactorial in nature and can be classified according
to its pathophysiology (nociceptive, neuropathic), cause
(related or unrelated to the disease and its treatment),
and the timing of its occurrence1,2 . Breakthrough pain
represents a key element of pain management in patients
with malignancies.
The first standardized definition of btcp was established by Portenoy et al.3 in 1990 and amended by Davies et
al.4 in 2009. According to those two groups, btcp is a temporary exacerbation of pain that occurs despite adequately
controlled background pain. Pain episodes occurring without background pain or with poorly controlled background
pain cannot therefore be classified as btcp. Figure1 sets
out the algorithm for the identification of btcp proposed
by Davies et al.4 in 2009.
The classical description of btcp includes rapid onset,
short duration, moderate-to-severe intensity, and frequent
occurrence. Although btcp can last up to 60 minutes, the
typical duration of an episode is 1530 minutes36. Another
important distinguishing characteristic of btcp is its rapid

Current Oncology, Vol. 23, No. 2, April 2016 2016 Multimed Inc.

Volitional incident pain (initiated by a voluntary act

such as walking)
Non-volitional incident pain (initiated by an involuntary act such as coughing)
Procedural pain (initiated by a therapeutic intervention such as wound dressing)

Approximately 50% of btcp episodes are precipitated

by a voluntary or involuntary event10.
The manifestation of btcp is inf luenced by numerous patient-, cancer-, and treatment-related factors and
changes throughout the course of the disease1. Factors
directly related to cancer include compression or infiltration of hollow organs, soft tissue, bones, and nerves.
Causes indirectly related to cancer include the consequences of disease (coughing because of lung cancer,
herpes zoster or post-herpetic neuralgia because of a
compromised immune system, back pain because of

FIGURE 1 Algorithm for the assessment of breakthrough cancer pain.

Reproduced with permission from Davies et al., 20094.

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MANAGEMENT OF BREAKTHROUGH CANCER PAIN, Daeninck et al.

immobility) or its treatment (investigational procedure,

chemotherapy, radiation, surgery), or both. Pre-existing
conditions or those that arise independently of cancer
(arthritis, migraine) are recognized as a source of pain
in 3% 10% of cancer patients1. Patient and physician
attitudes toward the disease and its treatment can also
contribute to breakthrough pain. Breakthrough cancer
pain is frequently misunderstood by health care professionals, leading to poor assessment and undertreatment.
Furthermore, given that cancer pain has physical, psychological, social, and spiritual dimensions, determination of the contribution of the various factors can be
difficult. Clinicians should also be aware of chemical
coping, because the reported incidence of pain in some
patients might reflect their psychological distress rather
than their physical pain11.

Education Points

Consensus Points

Differentiation between btcp and background pain

is challenging. Many clinicians perceive cancer pain
as one entity and often consider btcp to be part of
baseline pain. That belief likely contributes to a high
incidence of btcp, its under-recognition, and undertreatment. Adequate control of background pain is the
key characteristic that should be taken into consideration when assessing btcp.
End-of-dose pain is understood to be the reappearance
of background pain because of an insufficient dose of
around-the-clock opioids either in short- or long-acting
forms. The end-of-dose effect is often a result of a lack
of knowledge about pharmacokinetic parameters. It
and btcp have different causes and should be assessed
and treated differently.
Although mild pain (intensity 23 on a 10-point scale)
might not require immediate attention, it might be a
sign of progressive disease and, as such, it requires
proper follow-up.

FIGURE 2 Classification of cancer pain according to its occurrence.

*Predictable pain can be further divided into pain induced by a specific
procedure or treatment (for example, changing a wound dressing) and
pain induced by voluntarily movement (for example, walking). **Pain
precipitated by an involuntary act (coughing, bladder spasm, movement
during sleep).

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Health care professionals have to understand the pathophysiology of pain to be able to perceive that transient
sharp spikes of pain, as illustrated in Figure2, are separate entities with causes and manifestations that are
different from those of background pain. In addition,
btcp is multifactorial in nature; it should be treated
according to its suspected pathophysiology to optimally
reduce its incidence, prevalence, and severity.
Clinicians have to understand that not all incident pain
experienced by cancer patients can be categorized as
breakthrough pain. For example, movement-related
pain experienced by a patient with bone fractures who
does not require around-the-clock analgesia should
not be considered breakthrough pain. On the other
hand, incident pain, as described in this case, if present most of the day, should be treated as background
persistent pain.
Differentiation of end-of-dose pain from btcp could
require that health care professionals, caregivers, or
patients keep a log and document frequency, timing,
duration, severity, and trigger (if known) of pain episodes. Such documentation requires time and training, and in many instances might be compromised
by factors such as a patients cognitive functioning,
busy schedules and a lack of knowledge on the part
of residential care staff, or inadequate orders from
treating clinicians, underlining a clear need for education initiatives.

EPIDEMIOLOGY AND CONSEQUENCES

OF BTcP
The reported prevalence of btcp varies significantly across
studies and regions12, principally because of variability
in the definitions of btcp, study designs, methods used to
assess btcp, settings, and patient populations. According to
a recent systematic review of the published literature that
included nineteen studies and more than 6000 patients
with cancer pain, the prevalence of btcp ranges from 33%
to 95%, with an overall pooled prevalence of 59.2%12. That
finding is similar to the reported prevalence of breakthrough pain in patients with chronic non-cancer pain1315.
The prevalence of btcp is lowest in studies conducted
in outpatient clinics (39.9%) and highest in studies conducted in the hospice setting (80.5%)12. The higher reported
prevalence of btcp in the hospice setting has several possible explanations beyond the fact that the patients might
have more advanced disease. Compared with other specialists, most clinicians in hospices have more knowledge
and experience in recognizing btcp. Also, the era in which
a study was performed could be an important factor; the
btcp prevalence rate has decreased to 49% in the most
recent publications from 75% in studies published during
1990199412. The difference potentially reflects a better
understanding of the pathophysiologic mechanisms and
clinical features of btcp, the overall changes in its definition
and diagnosis, and more effective therapeutic approaches.
For example, improvements in diagnostic criteria might
have excluded several situations (end-of-dose failure, for

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MANAGEMENT OF BREAKTHROUGH CANCER PAIN, Daeninck et al.

instance) that were previously considered to be btcp. Better

control of background pain and use of co-analgesia could
also be a contributing factor.
According to a study conducted in 110 centres in
Italy, patients with btcp (n= 1801) are younger and have
more bone metastases and neuropathic pain 16 . That
observation might be a reflection of clinician reluctance
to prescribe opioids to younger patients and of the fact
that younger patients tend to be more active. However,
given that incident pain was not distinguished from
other types of pain, it is difficult to further validate the
latter assumption.
In a questionna ire completed by 1000 patients
(treated at 28 palliative care units in 13 European countries) about the characteristics of their btcp 10, 44% of
respondents reported incident pain, 42% reported spontaneous pain, and 14% indicated that they experienced a
combination of incident and spontaneous breakthrough
pain. Patients with incident pain reported that the pain
interfered mostly with their ability to walk and perform
daily activities; those with spontaneous pain said that
their pain interfered mostly with their mood and ability
to sleep.
A recent survey of cancer patients (n= 94) conducted
at four Canadian cancer centres revealed that, in approximately one half the patients, an episode of cancer pain
lasts about 60 minutes17. The average pain score was 7.8 on
a 10-point scale, indicating severe pain, and 96% of participants indicated that pain affected their activities of daily
living (>50% were unable to work or sleep). In a similar
study conducted in Europe, 32% of patients revealed that
their pain was so severe they want[ed] to die18. Patients
with btcp also report loss of control, changes in lifestyle,
and diminished quality of life19. In addition, for many
patients, pain is a reminder of the presence of cancer, and
they often associate the severity of pain with the severity
of their disease (that is, mild or no pain equals remission,
and severe pain equals progressive disease).
With regard to economic impact, btcp is associated
with an increased number of hospitalizations, longer
hospital stays, and more emergency room and physician
office visits, totalling to US$12,000 annually in costs for
patients with btcp compared with US$2400 annually
for those without btcp20. From the patient and caregiver
perspectives, btcp incurs significant personal expense,
including factors such as transportation to clinic or hospital, parking, change in medications, nonpharmacologic
therapies, and childcare21. For providers and institutions,
treatment of poorly managed btcp substantially raises the
costs of care and places additional demands on health
care resources21.

Education Points

Education initiatives for patients are necessary, because patients with a better understanding of the
causes of their pain will be better able to manage their
pain and properly use prescribed medications.
Clinicians should be aware of the significant burden
that btcp is causing to patients and their families
and should work closely with other members of their
health care team to alleviate that burden, reduce the
fears and anxieties of patients, and make patients as
comfortable as possible.
Additional education efforts are required to assist
clinicians in recognizing the underlying mechanisms
and pathophysiology of idiopathic btcp, because this
type of pain can have detrimental effects on the mood
and well-being of patients. Patients with spontaneous
unpredictable pain often live in fear and worry because
a sharp spike of pain can happen at any time, without
apparent cause. Thus, clinicians should strive to identify and, if possible, treat the pathophysiology behind
idiopathic pain so as to alleviate that psychological
burden from patients and their caregivers.

ASSESSMENT GUIDES AND TOOLS

The main objectives of clinical assessment of btcp are to

find a correctable cause, if possible;

differentiate baseline persistent pain from btcp; and
determine the pattern of pain.

Tablei lists potential questions for the assessment of btcp.

It has been reported that many palliative care nurses feel
challenged in differentiating btcp from poorly controlled
background pain 22. A recent survey of 104 nurses at 10
British palliative care services revealed that 82% of nurses
wanted more training in the assessment of btcp23. Another
survey of 1241 European nurses showed that although 39%
had no pain assessment tool to help distinguish between
types of pain, 95% of those who used a tool found it useful 24. Similarly, in Canada, as many as two thirds of nurses
use assessment tools and guidelines to help distinguish
between background pain and btcp25, finding those tools
or guidelines to be somewhat (55%) or very (42%) useful.

TABLE I Questions that can help in the assessment of breakthrough

cancer pain
Do you have episodes of severe pain?

Consensus Point

How many episodes do you usually have per week or per day?

What triggers an episode, if anything?

Approximately 60% of cancer patients in Canada

experience breakthrough pain, which significantly
affects quality of life, daily activities, and psychological well-being, because the intensity of pain is often
associated with the severity of the disease. This btcp
also poses a significant burden on caregivers and the
health care system.

Current Oncology, Vol. 23, No. 2, April 2016 2016 Multimed Inc.

How long does each episode last?

Can you describe how much an episode hurts on a scale of 010, if 0
is no pain at all and 10 is the worst pain imaginable?
Where is the pain?
What does the pain feel like? Is it similar to or different from your usual
baseline pain?

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The current literature contains no information about

the use of various tools by clinicians, likely reflecting the
fact that, because of their busy schedules, they assign the
pain assessment task to staff. That observation further
highlights the need for education initiatives that guide
nurses in the utilization of tools and clinicians in the interpretation of the information gathered. A diagnosis of btcp
is usually made based on multiple sources, but in patients
with normal cognitive functioning, self-report is the best
source of information about btcp26.
Overall, the tools for pain assessment can be divided
into unidimensional tools, multidimensional tools, and
pain diaries. Pain diaries provide a detailed patient-
reported account of the pains nature, duration, severity,
and predictability. If properly completed, the diary can
be useful in evaluating the frequency and intensity of
btcp over time27; however, patient compliance with diary
completion is typically poor.
The 3 unidimensional pain scales (Figure3) for pain
intensity measurementvisual analog scale (vas), numeric rating scale (nrs), and verbal rating scale (vrs)have
all been proved to be reliable and valid 28. The preference
of patients for a particular tool varies. For example, a vrs
tends to be preferred by older individuals and by those
with lower levels of education. However, in a systematic
review of 54 studies comparing unidimensional scales, a
nrs demonstrated better compliance in 15 of 19 studies
comparing it with a vas and a vrs, and it was the recommended tool in 11 studies on the basis of higher compliance rates, better responsiveness and ease of use, and
good applicability relative to a vas or vrs28. Brunelli et
al.29 also demonstrated that, in cancer patients, a nrs was
better than a vas in distinguishing between background

pain and peak pain intensity, with a lower proportion of

patients giving inconsistent evaluations (14% vs. 25%). In
addition a nrs showed higher reproducibility in the measurement of pain exacerbation. To that end, the European
Palliative Care Research Collaborative and the European
Association for Palliative Care Research Network recommend using a 010 nrs with standard endpoints of no
pain and pain as bad as you can imagine30 to measure
cancer pain intensity.
Multidimensional tools such as the Brief Pain Inventory31 and the McGill Pain Questionnaire32 provide specific information about factors such as the effect of pain on
daily function, the location of pain, and the effectiveness
of treatments. Those tools tend to be complex and to present challenges for patients with cognitive impairment. In
addition, none of the tools for general pain assessment
differentiate between btcp and background pain.
Two recently developed btcp-specific tools are the
Alberta Breakthrough Pain Assessment Tool (abpat) 33 and
the Breakthrough Pain Assessment Tool (bat) 34.
The abpat was developed using a Delphi process involving a literature review by an international group of
experts, followed by a pre-test with think-aloud interviews
of patients with btcp33. The patient self-reporting section
of the tool (15 questions) assesses the relationship of pain
flares to background pain, further probes for details about
sources of relief, and inquires about timing, frequency,
location, severity, quality, causes, and predictability of the
btcp. The tool was validated in 249 patients from 7 different centres35. Nearly all the participating patients (92.8%)
stated that the questions were easily understandable,
and 87.1% said that the tool explained the btcp problem.
Physicianpatient correlation tests showed statistical significance. The tool was also able to assess the satisfaction
of patients with their btcp medication. Use of the abpat to
evaluate the efficacy of breakthrough medication revealed
that 78.2% of patients claimed to have good pain relief, but
only 55.9% of patients were satisfied with the time of onset
of action for the medication.
The development of the bat followed a procedure similar to that of the abpat (literature review, Delphi process,
and semistructured interviews with patients experiencing
btcp) 34. The tool was also subjected to a series of psychometric tests for factor structure, validity (content and
construct), reliability (internal consistency, testretest),
and responsiveness to change. Where the abpat tool was
designed specifically for research purposes, the objective
of the bat was to facilitate the management of patients with
btcp in the clinical setting.

Consensus Points

FIGURE 3 Unidimensional pain scales.

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Breakthrough pain can be difficult to assess in the clinical setting. We recommend the algorithm proposed by
Davies et al.4 (Figure1) because it is widely used and
cited in the literature.
An assessment tool can be an effective way to evaluate
and document the characteristics of btcp. However,
the tool has to be quick and simple to use. We recommend the 0-10 nrs because it is currently accepted as
the standard.

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Because a thorough assessment is a key step toward

adequately managing btcp, clinicians should strive
to identify the origin of the pain (cancer, treatment,
comorbidities, or some combination thereof ), the
pathophysiology (nociceptive, neuropathic, or mixed),
and any other factor that could affect treatment.
We recognize that recently developed btcp assessment tools have the potential to be used for clinical
and teaching purposes. However, follow-up studies
of the outcomes in patients who are assessed and
subsequently managed using those tools are needed.

Education Points

Education initiatives to guide health care personnel in

the use of btcp assessment tools are needed. Furthermore, although the abpat was developed for research
purposes, and the bat, for clinical purposes, those tools
could be used to aid in the decision-making process
in complicated cases. Thus, palliative care nurses and
clinicians have to be trained in how to use those tools
and the situations in which the tools can be helpful.
The availability of btcp assessment tools and the education initiatives relating to their use will also build
awareness that btcp is a unique entity and not just a
part of background cancer pain.

CONVENTIONAL MANAGEMENT OF BTcP

According to World Health Organization guidelines, opioids are the mainstay of analgesic therapy in cancer patients and are classified according to their ability to control
pain36. Morphine is traditionally considered the first opioid
choice for the treatment of moderate-to-severe cancer pain,
and it is the most studied opioid37,38. However, since the
mid-1990s, the use of other opioids such as oxycodone, fentanyl, hydromorphone, and methadone have significantly
increased. Immediate-release oral opioids are currently the
approach most commonly used to manage btcp.
Conventional treatment of btcp often involves taking,
as rescue medication, an extra dose (at 5%20% of the total daily dose) of the opioid used around the clock to relieve
background pain39,40. That approach, which is based entirely on many years of clinical experience, might not always
offer the optimal speed of onset and the duration needed
to match the rapid-onset nature of an episode of btcp. Because the pain relief could be urgently required, routes of
administration designed to deliver drugs rapidly (that is,
parenteral or transmucosal) are then chosen. A few studies
have looked at the sublingual use of morphine; however,
because of its hydrophilic properties, morphine is not the
best candidate for that route of administration41. It has been
suggested that sublingual methadonebecause of its good
bioavailability and highly lipophilic nature, allowing it to
be readily absorbed via the sublingual mucosamight be
an interesting option for breakthrough pain4244.
The use of the same opioid treatment for baseline
persistent pain and btcp could offer some advantages, such
as easier titration of the around-the-clock dose and better
management of opioid side effects; however, that approach
might not always be feasible, because the pharmacokinet-

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ics of around-the-clock opioids might not match the onset

of the btcp episode. As mentioned, oral administration
of morphine, although effective in the management of
chronic pain, might not be suitable for the treatment of
btcp because of its particular pharmacokinetic profile (hydrophilic nature, start of analgesic activity only 30 minutes
after administration, and relief duration of at least 4 hours).
Oxycodone and hydromorphone have similar properties.
It is also speculated that the use of opioids with different
pharmacologic properties and modes of action than the
agent used for around-the-clock analgesia might be beneficial, because alternative pain pathways might be targeted.
However, a lack of clinical trials comparing various btcp
management strategies contributes to ongoing dilemmas
about the approach to use in particular situations. Thus, it is
important to emphasize that the choice of opioids for basal
pain and for btcp should be based on clinical judgment and
be personalized according to the patients clinical needs,
characteristics, compliance, and preference.
Some episodes of btcp can be treated with non-opioids,
such as nonsteroidal anti-inflammatory drugs, steroids,
bisphosphonates, or tramadol38,4547. Tramadol is a centrally acting analgesic with weak mu-receptor affinity that
also inhibits the reuptake of norepinephrine and serotonin45. Steroids can help with pain from nerve and spinal
cord compression, liver pain, and bone pain, and are
particularly effective at reducing pain caused by swelling
and inflammation46. Because bisphosphonates lower high
levels of calcium in the blood, they can help with bone pain
in patients with bone metastases from various types of
cancers (breast, prostate, melanoma)47 or with cancers that
begin in the bone, such as multiple myeloma48.
Although nonpharmacologic approaches to management of btcp have not been evaluated in clinical trials, they
are often used by patients and recommended by treating
clinicians. Possibilities include physiatry techniques 49,50
(application of ice or heat, orthotic devices, massage and
physical therapy, transcutaneous electrical nerve stimulation, percutaneous electrical nerve stimulation) and
surgical interventions.
Anesthetic approaches such as chemical neurolysis
and infusion of local anesthetics, opioids, and clonidine by
epidural catheter are useful in the treatment of persistent
pain, but can also be beneficial in alleviating btcp5153. A
percutaneous cordotomy can be used to treat refractory
incident pain from bone metastases. Intrathecal phenol
block and pituitary ablation have also been used to treat
refractory breakthrough pain. However, the results of those
invasive procedures are often suboptimal when the risks
of adverse effects are considered54.

Consensus Points

The first step in the management of cancer pain should

be an attempt to prevent the occurrence of pain by
taking into consideration its causes. Thus, appropriate
therapeutic approaches that do not necessarily include
opioids (for example, radiation and bisphosphonates
for bone pain) should be considered. The dose of background analgesia and the management of background
pain should be optimized before attempting to treat btcp.

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It is reasonable to use up to 20% of the total daily opioid

dose to treat btcp, because, historically, that approach
has been shown to be effective in a high proportion
of patients. Clinicians can consider using different
formulations for background and breakthrough pain.
Although no clinical trials have currently demonstrated that the two-formulations approach is more
effective, the suggested scientific rationale is that, because of different mechanisms of action and targeting
of different pathways, such an approach could result
in improved pain control.

Education Point

Conventional treatment of btcp has involved the use

of an extra rescue dose (at 5% 20% of the total daily
dose) of the opioid used to manage background pain,
or of an equianalgesic dose of another agent (transdermal fentanyl and oral morphine, for example). Because many clinicians find it challenging to calculate
the appropriate opioid dose for the management of
breakthrough episodes based on the around-the-clock
total opioid dose, additional education initiatives
might be required.

CONTEMPORARY APPROACHES TO
THE MANAGEMENT OF BTcP WITH
RAPID-ONSET OPIOIDS
As already mentioned, transmucosal administration has
the potential to deliver drugs more rapidly than oral administration can. The oral mucosa are easily accessible, more
permeable than skin, and more richly supplied with blood,
presenting an attractive route for drug delivery and allowing for lipophilic opioids to bypass first-pass metabolism.
Fentanyl, a completely synthetic mureceptorstimulating
opioid, is one of the most lipophilic opioid analgesics, with
a potency 100 times that of morphine55. Its lipophilicity
enables rapid diffusion across the bloodbrain barrier, and
therefore diffusion into central nervous system structures.
Fentanyl also quickly crosses cellular barriers, providing
broad tissue distribution and rapid onset of action.
The potency, lipophilicity, and clinical efficacy of fentanyl have made it the object of intense interest for a variety
of transmucosal applications55. Because both its onset of
action and its peak plasma concentration depend on the
dose and method of delivery, achievement of analgesia occurs within 12 minutes after intravenous administration,
1015 minutes after buccal transmucosal delivery, and 14
hours after transdermal application. Its duration of action
is usually 24 hours after intravenous or transmucosal administration. The drugs half-life is longer with transdermal
administration because of drug deposition in the lipids
of the skin, through which it is slowly released over time.
As with many opioids, fentanyl is metabolized mainly
via the cytochrome P450 pathway, and drug interactions
are a possibility when fentanyl is given concurrently with
other drugs affecting cytochrome P3A456. Thus, caution
is required, because co-administration could result in an
increase in fentanyl plasma concentration sufficient to
cause potentially fatal respiratory depression.

102

Oral transmucosal fentanyl citrate was one of the

first transmucosal drug formulations, developed as a
fentanyl-impregnated lozenge on a stick 55. One quarter
of the fentanyl in this formulation is absorbed rapidly
through the buccal mucosa, and another 25% of the total
dose is absorbed through the gastrointestinal tract after
it has been swallowed 57. Clinical experience with the
formulation provided some valuable insights, including
the observations that there is no meaningful relationship
between the successful dose of oral transmucosal fentanyl
citrate and the background opioid, and that separate titration is necessary5860. In addition, clinicians learned that
transmucosal fentanyl should never be administered to
opioid-nave patients. The current recommendation is that
patients should already be receiving an equivalent daily
dose of morphine of at least 60mg 61,62. Titration strategy
should follow the manufacturers recommendations, and
the maximum daily use should not exceed 4 doses.
Fentanyl buccal tablets are formulated for enhanced
mucosal permeation by the manipulation of pH, leading
to approximately 50% transmucosal absorption61,63. The
dissolution process takes 1425 minutes and the time to
maximum plasma concentration is 3545 minutes61,63. Pain
relief has been observed to begin as early as 10 minutes after
administration and to last throughout the 120-minute observation period64. In two randomized controlled trials that
compared fentanyl buccal tablets with placebo, btcp relief
attained significantly favoured fentanyl buccal tablets64,65.
Fentanyl sublingual tablets contain water-soluble particles that are coated with fentanyl and a muco-adhesive
agent to help keep the tablet under the tongue, reducing
the risk of swallowing 62. Overall bioavailability is 54%.
In a randomized placebo-controlled study of fentanyl
sublingual tablets in 131 adult patients with btcp, use of
the tablets resulted in significant improvements in pain
intensity and relief compared with placebo66. In phaseiii
studies evaluating the long-term effectiveness of transmucosal immediate-release fentanyl, patients reported high
levels of satisfaction with the formulation65,67.
Intranasal fentanyl spray was developed as an alternative method of delivering fentanyl in patients with xerostomia or salivary gland dysfunction. It has a bioavailability
of approximately 89% 68. Its onset of action occurs within
approximately 7 minutes, and its duration of analgesic
effect is approximately 1 hour 66. The efficacy of intranasal
fentanyl spray 50200g per spray was demonstrated in a
phaseiii randomized trial that included 120 opioid-tolerant
patients with btcp69.
Transmucosal fentanyl formulations are generally
well-tolerated, with the adverse events typical of opioids, including nausea, constipation, somnolence, and
headache 64,65,67,69.
Although placebo-controlled randomized clinical
trials have demonstrated the efficacy of all the available
transmucosal fentanyl formulations for btcp, the lack of
head-to-head comparisons makes it challenging for physicians to select an appropriate approach based on efficacy
alone. Tableii provides key pharmacokinetic parameters
for various fentanyl formulations used for breakthrough
pain. Meta-analyses have been attempted, but a firm conclusion cannot be made because of differences between the

Current Oncology, Vol. 23, No. 2, April 2016 2016 Multimed Inc.

Current Oncology, Vol. 23, No. 2, April 2016 2016 Multimed Inc.

400g, and 800g)

NA; prescribing
information states that
bioavailability is 120%
of that for oral transmucosal fentanyl citrate

89%

76%

54%

71%

NA

Not relevant

NA

NA

51% though
buccal mucosa

48% though
buccal mucosa

25% though
buccal mucosa

Fraction absorbed
transmucosally

0.330.35 hours for

doses from
100g to 800g

1215 Minutes for

doses from
50g to 200g

0.691.25 hours
(range: 0.084.00 hours)
for doses from 100g
to 800g

3060 Minutes
(range: 16240 minutes)
for doses from 100g
to 800g

60 Minutes
(range: 45240 minutes)
for 800g dose

3545 Minutes
(range: 20181 minutes)
for doses from 100g
to 800g

2040 Minutes
(range: 20480 minutes)
for doses from 200g
to 1600g

Tmax

NA

1.2510.38ngh/mL for
doses from 100g to
800g

0.9748.95ngh/mL for
doses from
100g to 800g

3.4620.43ngh/mL for
doses from
200g to 1200g

0.989.05ngh/mL for
doses from
100g to 800g

102ngmin/mL for 200g

to 1026ngmin/mL
for 1600g (AUC01440)

AUC0c

351.52844.0pg/mL for 2460.517,272ngh/mL

doses from
for doses from
100g to 800g
100g to 800g

0.351.2ng/mL
for doses from
50g to 200g

0.201.61ng/mL
for doses from
100g to 800g

0.1871.42ng/mL
for doses from
100g to 800g

0.382.19ng/mL
for doses from
200g to 1200g

0.251.59ng/mL
for doses from
100g to 800g

0.392.51ng/mL
for doses from
200g to 1600g

Cmax

1524.9 Hours
for doses from
100g to 800g

Elimination
ty 34 hours

5.2511.99 Hours
for doses from
100g to 800g

5.0210.1 Hours
for doses from
100g to 800g

Approximately
14 hours
(terminal ty)

2.6311.70 Hours
for doses from
100g to 800g

193386 Minutes
for doses from 200g
to 1600g (mean)

Reproduced with permission from Smith, 201368.

Currently, only Fentora and Abstral are approved by Health Canada.
c Unless otherwise stated.
d Cephalon, Malvern, PA, U.S.A.
e BioDelivery Sciences, Raleigh, NC, U.S.A.
f Sentynl Therapeutics, Solana Beach, CA, U.S.A.
g INSYS Therapeutics, Phoenix, AZ, U.S.A.
h Takeda Pharmaceuticals International, Zurich, Switzerland.
i Depomed, Newark, CA, U.S.A.
Tmax= time taken to reach Cmax; Cmax= maximum plasma drug concentration; AUC0= area under the plasma concentrationtime curve from time zero to infinity; t= half-life; NA= not available.

100g, 200g,

(enabling dosing at

100g, 400g

Fentanyl pectin nasal spray (Lazandai)

200g

50g, 100g

Intranasal fentanyl spray (Instanylh)

800g

400g, 600g

100g, 200g

Sublingual fentanyl spray (Subsysg)

600g, 800g

300g, 400g,

100g, 200g,

Sublingual fentanyl tablet (Abstralf)

1200g

600g, 800g,

200g, 400g,

Fentanyl buccal soluble film (Onsolise)

600g, 800g

300g, 400g,

100g, 200g,

65%

50% compared with

intravenous fentanyl

Oral transmucosal fentanyl citrate (Actiqd)

200g, 400g,
600g, 800g,
1200g, 1600g

Fentanyl buccal tablets (Fentorad)

Absolute
bioavailability

Agentb and available strengths

TABLE II Key pharmacokinetic parameters of various fentanyl formulations for breakthrough pain6,8,a

MANAGEMENT OF BREAKTHROUGH CANCER PAIN, Daeninck et al.

103

MANAGEMENT OF BREAKTHROUGH CANCER PAIN, Daeninck et al.

populations studied and the trial designs. In the absence

of clear data about the relative efficacy of the products,
prescribing decisions can be based on the advantages and
disadvantages of the various routes of administration. A recent review of the pharmacokinetic profile of transmucosal
fentanyl formulations revealed 3 different concentration
profiles (Figure4)70 :

Very rapid rise and short duration (with intranasal

administration)
Rapid increase and sustained intensity (with buccal
delivery)
Slower onset and longer duration

Thus, the choice in the clinic might be driven by the

pain syndrome experienced by the patient. For example,
for very-rapid-onset and short-duration pain, a product
with a rapid rise in concentration might be beneficial,
while a rapid-but-sustained concentration profile appears
to be more suitable for pain with fast onset but prolonged
duration. For pain with a slower onset and longer duration,
the review suggests consideration of the slower-andlonger profile achieved with oral transmucosal fentanyl
citrate. However, the latter formulation is not available
in Canada.
Although current guidelines vary in their methodology, rigour, and expert working group composition, they
all include the use of rapid-onset opioids (transmucosal
fentanyl formulations) tailored to the unique btcp presentation7174. The inclusion of fentanyl transmucosal
formulations in the present guideline is based on two recent meta-analyses that favoured that approach over the
traditional ones74,75.

Consensus Points

Two recent meta-analyses indicate the benefits of

transmucosal fentanyl formulations over traditional
approaches, especially when treating pain that has
rapid onset and short duration.

FIGURE 4 Pharmacokinetic profile of transmucosal fentanyl formulations. Reproduced with permission from Moore et al., 201270.

104

The pharmacokinetics or pharmacodynamics of the

3 available fentanyl formulations should be taken
into consideration when deciding on the therapeutic
approach for a specific type of btcp. The pharmacologic properties of the fentanyl formulation should be
matched with the characteristics of the btcp, including its onset and duration.
Transmucosal fentanyl formulations should never be
used in opioid-nave patients.
To assess the effectiveness of the selected approach for
the management of btcp, the same assessment tools or
scale should be used both before and after treatment.

Education Point

Additional efforts are required to build awareness

among health care professionals, especially pharmacists, that the various new formulations of transmucosal fentanyl are not equianalgesic and are therefore
not interchangeable.

MANAGEMENT OF BTcP:
CANADIAN PERSPECTIVE
In Canada, the most common approach to the management of btcp includes the use of the traditional shortacting opioids (morphine, hydromorphone, oxycodone).
Currently, two new transmucosal fentanyl products, administered sublingually (Abstral: Sentynl Therapeutics,
Solana Beach, CA, U.S.A.) or buccally (Fentora: Cephalon,
Malvern, PA, U.S.A.), are approved by Health Canada 55.
The dosing and titration process required with the new
products often presents challenges for both the patient
and the health care provider, because the initially chosen
dose is often inadequate to control the pain and rescue
medication has to be taken. A higher transmucosal fentanyl dose is then used for future breakthrough episodes,
but it cannot be taken until after 4 hours have passed.
Titration usually takes 12 days and often requires regular contact with the patient for reassurance and advice.
Some investigators challenge this titration principle,
especially for patients taking a higher background opioid
dose, because those patients also need higher background
doses76. However, data to recommend a proportional-dose
approach are limited.
Several current provincial guidelines for the management of cancer pain in Canada include a brief discussion
on the treatment of btcp7779, but no uniform recommendations for the management of btcp have been made at the
national level. That lack of a national recommendation,
together with the unequal access to pain medication across
the country, contributes to regional and provincial variability in the management of btcp. Furthermore, although
immediate-release morphine, hydromorphone, and oxycodone are recommended by the Canadian Agency for Drugs
and Technologies in Healths Common Drug Review and
are listed on most provincial formularies, transmucosal
fentanyl formulations are not recommended, and access
to those agents is limited. Higher costs of transmucosal
fentanyl formulations compared with other available oral
opioids, together with a lack of direct comparisons, are the

Current Oncology, Vol. 23, No. 2, April 2016 2016 Multimed Inc.

MANAGEMENT OF BREAKTHROUGH CANCER PAIN, Daeninck et al.

main reasons for unfavourable recommendations. In addition, the Canadian Drug Expert Committee stated that
the abuse potential with these agents is also considerable.
Because of a lack of access to one of the approved transmucosal fentanyl formulations, many Canadian hospitals
use an off-label sublingual or injectable sufentanil55. An
oral syringe or a spray bottle is used to deposit the sufen
tanil under the tongue. This relatively inexpensive method
is complicated in terms of preparation and consistency of
dosing, and its use should be limited to palliative care units.
Another frequent approach is the off-label use of intranasal injectable fentanyl or sufentanil (or both) through
a Mucosal Atomization Device (Teleflex, Morrisville, NC,
U.S.A.) 80. The ideal volume for intranasal administration is
0.20.3mL, because volumes above 0.5mL will not be well
absorbed, tending to drip down the back of the throat and
be swallowed. In certain patients, the use of sufentanil is
therefore recommended.
A recent study in the province of Quebec that used the
Rgie de lassurance maladie du Qubec database revealed
that, in a cohort of 48,420 people dying of cancer, almost
60% did not fill their community-based opioid prescriptions
on a regular basis. On the other hand, in patients who did
fill their prescriptions, the opioid dose tended to increase
significantly over time (Figure5). That observation might be
the result of increased pain because of disease progression,
development of opioid tolerance, or the attempt by clinicians
to treat btcp by increasing the dose of background opioids.
Assessment of the development of opioid tolerance in cancer
patients is somewhat difficult in clinical practice because
of an inability to distinguish whether the increasing opioid
requirement is the result of disease progression, a true
pharmacologic tolerance, or opioid-associated hyperalgesia.
It is also interesting to note that the first prescriber of
opioids for cancer patients in Canada is the family physician (37% of cases), followed by the medical oncologist
(19%)17. However, adjustments in the opioid prescription

are more likely to be made by oncology staff. A recent

survey also revealed that the most commonly used opioid
for background cancer pain in Canada is hydromorphone
(26%), followed by oxycodone (19%), morphine (14%), and
fentanyl (14%)17. Hydromorphone (37%) and morphine
(22%) are also the drugs most commonly used for breakthrough pain. The survey also indicated the need for more
effective and faster-acting pain relief medications; only
37% of patients indicated that they were satisfied with
the speed of pain relief, and only 19% indicated very good
level of relief. When asked to specify the most important
features of a new treatment for breakthrough pain, 47% of
patients indicated the ability to relieve pain completely,
and 43% highlighted the ability to relieve pain quickly. Of
every 5 patients, 4 (80%) said that they were willing to try
transmucosal products.

Consensus Point

Although injectable fentanyl and sufentanil are used

sublingually or intranasally off-label in the hospital
setting, where trained personnel can administer them,
this practice is not recommended for out-of-hospital
settings. Only tested applications should be used in
home and hospice settings, especially given that approved and safe drug delivery systems are available.
Clinicians should keep in mind that fentanyl is absorbed quickly and that the time to maximum plasma
concentration can be very rapid. Serious consequences
can ensue during off-label use by inexperienced health
care professionals or in an inappropriate setting.
When assessing the abuse potential for either long- or
short-acting opioids, the treating clinician should keep
in mind that all opioids have the potential to activate
the reward system in the brain. Although the pharmacology and the mechanism of action of fentanyl meet
all criteria for potential to abuse, there is no evidence
that transmucosal formulations are more addictive.
Nasal administration might be more challenging,
because patients and caregivers might not be certain
whether the appropriate dose has been given.
Concerns related to opioid abuse and dependence
should not prevent clinicians from using opioids in
patients who have only a few months to live. Making
such patients as comfortable as possible should be the
top priority.

Education Points

FIGURE 5 Patterns of community-based opioid prescription filling in

people dying of cancer during their last 11 months of life in the province
of Quebec. Reproduced with permission from Gagnon et al., 201581.

Current Oncology, Vol. 23, No. 2, April 2016 2016 Multimed Inc.

Fear of opioid use is an ongoing issue, because addiction- and abuse-related concerns lead to continued
reluctance on the part of many clinicians to prescribe
opioids. Thus, additional education efforts and initiatives are needed to lessen such concerns so that cancer
patients are provided with adequate pain control.
Additional efforts are needed to identify the true reasons
for the continuous increase in opioid dose in end-of-life
cancer patients. If the increase in dose is indeed related to
attempts by clinicians to control breakthrough pain, then
education initiatives about alternative options, including
use of the short-acting fentanyl formulations, are needed.

105

MANAGEMENT OF BREAKTHROUGH CANCER PAIN, Daeninck et al.

SUMMARY
Management of btcp remains a balancing act. It is influenced by the nature of pain itself, but also by access to
therapies, fear of addiction, and medication tolerance.
When assessing btcp, the cause of the baseline pain has to
be taken into consideration. Management considerations
for btcp depend on its pathophysiology, the setting in which
the patient is treated, and the stage of the disease.
The traditional use of oral opioid formulations and the
use of newer transmucosal fentanyl formulation are both
valid options, provided that background pain is adequately
controlled and that treatment of btcp is individualized
according to patient needs and the unique characteristics
of the pain episodes.

Consensus Recommendations
The medical community has to be aware that btcp
is a prevalent condition with detrimental consequences for patients, caregivers, and the health
care system.
The first step in diagnosing and treating btcp is to
ensure that background pain is properly addressed.
The experience of pain in cancer patients is multifactorial and varies from patient to patient. Clinicians have to recognize and differentiate between
neuropathic and other types of cancer pain so as to
select proper therapy.
Clinicians should be aware of the two recently developed assessment tools for btcp that can be used
in specific complicated situations with challenging
diagnoses. However, for daily routine practice, simpler
tools and scales such as the diagnostic algorithm proposed by Davies et al.4 and a nrs are recommended.
Clinicians should strive to identify and treat all underlying causes of pain, regardless of whether the pain is
predictable or unpredictable. Some types of pain are
unpredictable despite the fact that a trigger (coughing,
for instance) is identifiable. In such cases, clinicians
should treat the causative event (that is, the cough).
Breakthrough cancer pain can be effectively managed
with immediate-release oral opioids or with transmucosal fentanyl preparations.
For some types of btcp, transmucosal fentanyl formulations are preferable to immediate-release oral
opioids because of more rapid onset of action and
shorter duration of effect.
The cost of transmucosal fentanyl preparations should
not impede their use, especially taking into consideration that many patients in need of those medications
have a very short life expectancy and that the medication will be needed for only a brief period of time.
Policymakers should keep those factors in mind when
making their listing recommendations.
As for all opioids, the risks of addiction and diversion
should be taken into consideration, and appropriate
assessment and monitoring should be applied. Again,
addiction concerns should not prevent clinicians
from using opioids in patients who have only few
months to live.

106

ACKNOWLEDGMENTS
The meeting that produced the recommendations presented here
was organized by snell Medical Communication, and funding for
the meeting was provided by Teva Canada Innovation. Honoraria
were provided to the participants to create and present slides to
generate discussion. The funding also provided the authors with
the services of an experienced and qualified medical writer to
ensure a professional manuscript. The medical writer, solely under
the direction and outline of the authors, assisted in researching
the topic and preparing a first draft. At no time did the medical
writer have any involvement in determining the content of the
manuscript. The authors gratefully acknowledge the contribution
of Radmila Day in the drafting of the manuscript.
CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncologys policy on disclosing conflicts of interest, and we declare the following interests:
In addition to participation in the meeting, PD reported receiving
honoraria from Tweed (speaker fees), Prairie Plant Systems (education advisory board), and Bonify (scientific advisory board), and
RG reported receiving honoraria from Purdue Pharma (education
events). BG is a recipient of a Chercheurclinicien Boursier award
from the Fonds de recherche du QubecSant. The other meeting
participants declare that they have no conflicts to report.
AUTHOR AFFILIATIONS
*University of Manitoba, Winnipeg, MB; Department of Family
Medicine and Emergency Medicine, Laval University, Quebec City,
QC; University of British Columbia, Vancouver, BC, and Division
of Palliative Care, Providence Health Care, Toronto, ON; Colchester East Hants Palliative Care Program, Truro, and Atlantic
Palliative Medicine Group and Dalhousie University, Halifax, NS;
|| Alan Edwards Pain Management Unit, McGill University, Montreal, QC; #Palliative Services, University Health Network, University
of Toronto, Toronto, ON; **McGill University, Montreal, QC.
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