BeCOn OWN Educational Program
Modules
Module 4
Breakthrough cancer pain (BTcP)
Date of preparation: June 2015 HQ/EFF/15/0024c
Contents
Overview of BTcP
Management of BTcP
Overview of BTcP
Definition of breakthrough cancer pain (BTcP)
The management of cancer-related breakthrough pain:
Recommendations of a task group of the Science Committee
of the Association for Palliative Medicine of Great Britain
and Ireland
“
A transient exacerbation of pain that occurs either
spontaneously, or in relation to a specific predictable or
unpredictable trigger, despite relatively stable and
adequately controlled background pain
“
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
Classification of BTcP
Spontaneous pain (idiopathic pain)
Episodes are not related to an identifiable precipitant, and so are unpredictable in
nature
Incident pain (precipitated pain)
Episodes are related to an identifiable precipitant, and so are somewhat predictable.
Subclassified as:
– Volitional incident pain –brought on by a voluntary act (e.g. walking)
– Non-volitional incident pain –brought on by an involuntary act (e.g. coughing)
– Procedural pain –related to therapeutic intervention (e.g. wound dressing)
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
Prevalence of BTcP
Pooled analysis of 19 observational studies
The overall pooled prevalence was 59.2%, with high
heterogeneity
The lowest prevalence rates were detected in studies
conducted in outpatient clinics (39.9%)
The highest prevalence was reported in studies
conducted in hospice (80.5%)
39.9%
in outpatient clinics
80.5% in hospice
More than one in two patients with cancer pain also experiences BTcP
Deandrea S, et al. J Pain Symptom Manage. 2014;47(1):57-76.
National Breakthrough Pain Study
Interview of 2198 patients with opioid-treated chronic pain
80% of patients reported BTP
Patients had a median of 2.0 episodes of BTP per day (range, 1-50) and a median
duration of BTP of 45 minutes (range, 1-720)
Compared with patients without BTP, patients with BTP had more pain-related
interference in function, worse physical health and mental health, more disability and
worse mood
BTP is highly prevalent and associated with negative outcomes.
Narayana A, et al. Pain. 2015;156(2):252-9.
Characteristics of BTcP
3 per
day
Median number of BTcP episodes
60
min
Median duration
10
min
Median time to peak intensity
Multicentre European study of BTcP in 320 patients
Davies A, et al. J Pain Symptom Manage. 2013;46(5):619-28.
BTcP has many causes
BTcP is not a single entity, but a spectrum of very different entities
BTcP is related to different causes
Treatment-related
Cancer-related
(e.g. radiation induced injury,
chemotherapy, surgery)
(e.g. inflammatory response,
nerve compression)
Concomitant illness
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
BTcP has complex pathophysiology
BTcP has different pathophysiologies
Nociceptive
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
Mixed
Neuropathic
The onset of BTcP is rapid, but variable
Time to peak intensity of BTcP
All BTcP
500
Spontaneous BTcP
Incident BTcP
461
Number of patients (n= 936)
450
400
350
300
250
200
234
159
150
131
111
100
48 44
50
74
39
24
40
62
24 14
0
0-5
min
6-10
min
11-15
min
16-20
min
0 0 0
21-25
min
72
51
26-30
min
3 0 3
13 10 2
31-40
min
41-50
min
Median time to peak intensity is 10 minutes
Study of 1000 cancer patients from 13 European countries
Davies A, et al. J Pain Symptom Manage. 2013;46(5):619-28.
34 27
51-60
min
31
13 14
>60
min
The duration of BTcP is extremely heterogeneous
Duration of untreated episodes
All BTcP
Spontaneous BTcP
Incident BTcP
Number of patients (n= 505)
140
115
120
100
80
87
77
63
60
50
46
40
20
73
68
63
29
18
19
37
28
33 31
14
4
13
8
0 0 0
0
0-10
min
11-20
min
33
23
21-30
min
31-60
min
61-90
min
91-120
min
121-150
min
151-180
min
5 6
>180
min
The median duration for all BTcP was 60 min (range <1 min to 360 min)
Study of 1000 cancer patients from 13 European countries
Davies A, et al. J Pain Symptom Manage. 2013;46(5):619-28.
BTcP: Italian Oncological Pain Survey (IOPS)
Italian survey of 1,412 cancer patients
Mean of 2.4 BTcP episodes/day
80.6% patients reported that BTcP had a significant negative impact on everyday life
The majority of patients reported a fast onset of BTcP, which was predictable in 50.7% of
cases, while BTcP with a gradual onset (>10 min) was less predictable (29%)
Mean duration of background pain was 3.5 months before assessment
Mean duration of any analgesic treatment was 2.5 months before assessment
BTcP started a mean of 2.2 months before assessment
Patients in palliative care units were older, had lower Karnofsky levels, a lower number
of BTcP episodes/day, a slower onset of BTcP onset and a less predictable BTcP
Mercadante S, et al. et al. Clin J Pain. 2015;31(3):214-21.
BTcP affects all areas of daily life
Interference with various aspects of daily living
2nd quartile
3rd quartile
Enjoyment of life
Sleep
Relations with other
people
Normal work
Walking ability
Mood
General activity
0
1
2
3
4
5
6
Numerical rating (0-10)
Study of 1000 cancer patients from 13 European countries.
Davies A, et al. J Pain Symptom Manage. 2013;46(5):619-28.
7
8
9
10
BTcP has widespread implications
Depression
Anxiety
Healthcare costs
Increases
Activities
Social relationship
Working
Affects
BTcP
Affects
Sleep
Walking
Reduces
Quality of life
Satisfaction with therapy
EONS. Breakthrough cancer pain guidelines 2013.
Available at: http://www.cancernurse.eu/documents/EONSBreakthroughCancerPainGuidelines.pdf. Accessed 13 Apr 2015.
Management of BTcP
General considerations on management of
breakthrough pain
The aim of breakthrough pain management is to reduce the intensity, severity,
and impact of pain
Management involves:
1. general assessment (e.g. pain assessment, explanation)
2. lifestyle changes (e.g. coping strategies)
3. management of reversible causes (e.g. incident pain precipitants)
4. modification of the pathological processes (e.g. antineoplastic therapies)
5. symptomatic management of BTcP (e.g. pharmacological and non-pharmacological)
6. reassessment (e.g. evaluation of pain and management)
Successful management is best achieved by thorough assessment, good
communication, reassurance about pain relief and encouraging patient and
carer participation
Zeppetella G. Curr Opin Support Palliat Care. 2009;3(1):1-6.
Non-pharmacological methods for management of
breakthrough pain
A variety of non-pharmacological methods are used by patients, including:
Rubbing/massage
Application of heat
Application of cold
Distraction techniques
Relaxation techniques
However, there is relatively little evidence to support the use of these
interventions in the treatment of breakthrough pain episodes
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
Algorithm for diagnosing patients with BTcP
Does the patient have background pain?
Background pain = pain present
for >12 hour/day during previous week
(or would be present if not taking analgesia)
YES
Is the background pain adequately controlled?
Adequately controlled = pain rated as “none”
or “mild”; but not “moderate” or “severe”
for >12 hour/day during previous week
NO
Patient does not have
breakthrough pain, but does
have uncontrolled
background pain
YES
Does the patient have transient
exacerbations of pain?
YES
PATIENT HAS BREAKTHROUGH PAIN
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
NO
PATIENT DOES NOT HAVE
BREAKTHROUGH PAIN
NO
More effective management of BTcP requires asking
the right questions
An important consideration for adequate pain control in patients with cancer
is appropriate and regular assessment of pain
Onset of pain?
Exacerbating factors?
Frequency of pain?
Relieving factors?
Site of pain?
Response to analgesics?
Radiation of pain
Response to other interventions?
Quality (character) of pain?
Associated symptoms?
Intensity (severity) of pain?
Interference with activities of daily living?
Duration of pain?
Asking key questions can provide important insights into the patient’s pain
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
The Breakthrough Pain Assessment Tool (BAT)
A fully validated clinical assessment tool for breakthrough pain in cancer
patients
The BAT comprises 14 questions
Measures 2 to 3 underlying pain dimensions based on analysis of
generic cancer pain instruments
Queries BTcP frequency, intensity, duration and interference
The BAT can facilitate the management of patients with breakthrough cancer pain in a
clinical setting
Webber K, et al. J Pain Symptom Manage. 2014;48(4):619-31.
EONS: Management of BTcP
The aim of BTcP management is to reduce the intensity, severity and effect of
each pain episode, and to lessen the impact of BTcP on patients’ quality of life.
The management of BTcP should be individualised, with the optimal approaches depending
on:
Pain-related factors
– Aetiology of pain (cancer-related, treatment-related, concomitant illness)
– Pathophysiology of pain (nociceptive, neuropathic, mixed)
– Clinical features of pain
Patient-related factors
– Stage of the disease (early, advanced)
– Performance status of the patient (good, poor)
– Personal preferences of the patient
Breakthrough cancer pain guidelines 2013. European Oncology Nursing Society.
Available at: http://www.cancernurse.eu/documents/EONSBreakthroughCancerPainGuidelines.pdf. Accessed 12 Mar 2015.
APM Recommendations
1. Patients with pain should be assessed for the presence of breakthrough pain (grade of
recommendation: D)
2. Patients with breakthrough pain should have this pain specifically assessed (D)
3. The management of breakthrough pain should be individualised (D)
4. Consideration should be given to treatment of the underlying cause of the pain (D)
5. Consideration should be given to avoidance / treatment of the precipitating factors of
the pain (D)
6. Consideration should be given to modification of the background analgesic
regimen/“around the clock” medication (D)
APM, Association of Palliative Medicine
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
APM Recommendations
7. Opioids are the “rescue medication” of choice in the management of breakthrough
pain episodes (D)
8. The dose of opioid “rescue medication” should be determined by individual titration
(B)
9. Non-opioid analgesics may be useful in the management of breakthrough pain
episodes (D)
10. Non-pharmacological methods may be useful in the management of breakthrough pain
episodes (D)
11. Interventional techniques may be useful in the management of breakthrough pain (D)
12. Patients with breakthrough pain should have this pain specifically re-assessed (D)
APM, Association of Palliative Medicine
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
EONS: the ideal treatment for BTcP
The ideal treatment for most BTCP episodes is a rescue dose of a medication
with the following features:
Effective (a strong opioid)
Pharmacokinetic properties that closely match the temporal characteristics of a BTcP
episode, i.e. rapid onset with a relatively short duration of action
Patient-friendly – non-invasive, simple to administer
Minimal adverse effects
Cost-effective
Breakthrough cancer pain guidelines 2013. European Oncology Nursing Society. Available at:
http://www.cancernurse.eu/documents/EONSBreakthroughCancerPainGuidelines.pdf. Accessed 12 Mar 2015.
Characteristics of immediate-release opioids used in
BTcP
Immediaterelease opioid
Onset of
analgesia
Duration
of effect
Morphine (oral)
30−40 min
4 hr
A - available in multiple dosage
forms, liquid concentrate
D - slow onset of analgesia for
idiopathic BTP
Oxycodone (oral)
30 min
4 hr
Same as morphine
4 hr
D - no liquid concentrate, slow
onset of analgesia for idiopathic
BTP
Hydrophilic
30 min
Hydromorphone (oral)
Lipophilic
Advantages (A)/Disadvantages
(D)
Methadone (oral)
~10−15 min
4−6 hr
A - faster onset of analgesia in one
small study
D - complex pharmacology,
pharmacokinetics
Fentanyl (transmucosal)
~ 5−10 min
1−2 hr
A - faster onset of analgesia
D - requires ongoing patient
cooperation in use
Bennett D, et al. P&T. 2005;30:354-361.
Temporal relationship between BTcP episode and oral
morphine treatment
Duration effect
oral morphine
Peak effect
oral morphine
Onset effect
oral morphine
Duration of
breakthrough pain
0
30
60
90
120
150
180
210
240
270
Time (min)
A slow onset of action (analgesia: 20-30 min; peak analgesia: 60-90 min) results in
delayed or ineffective analgesia, while the prolonged duration of effect (3-6 hr) results
in ongoing adverse effects
Davies A, et al. Br J Nurs. 2011;20(13):803-4, 806-7.
Treatment strategies for BTcP
Pain or analgesic intensity
Pain or analgesic intensity
10
9
8
7
6
5
4
3
2
1
0
12 3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12
am am am am pm pm pm pm am am am am pm pm pm pm am
Pain or analgesic intensity
ATC ER Opioid Alone
10
9
8
7
6
5
4
3
2
1
0
12 3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12
am am am am pm pm pm pm am am am am pm pm pm pm am
10
9
8
7
6
5
4
3
2
1
0
12 3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12
am am am am pm pm pm pm am am am am pm pm pm pm am
BTcP has a time profile that is different from that
of chronic persistent pain and should therefore be
managed differently
ATC ER Opioid + IR Opioid
Treatment of BTcP with oral immediate release
opioids can take 30-45 minutes to produce an
analgesic effect, which lasts for 3-6 hours
ATC ER Opioid + ROO
Control of background pain with the same, lower
dose of an around-the-clock extended release
opioid with BTcP managed using a transmucosal
immediate-release fentanyl opioid minimises total
opioid exposure while reducing BTcP
Simon SM, Schwartzberg LS. J Opioid Manag. 2014;10(3):207-15.
Currently available rapid-onset opioid formulations
NASAL SPRAY
BUCCAL
SUBLINGUAL
 Tablet
 Effervescent tablet
 Spray*
 Lozenge
 Effervescent tablet
 Film
Several formulations of ROOs are available, which are characterised by a rapid
onset of action (within minutes) and typically administered via a non-invasive
transmucosal route
*Not available in the EU.
Simon SM, Schwartzberg LS. J Opioid Manag. 2014;10(3):207-15.
Considerations for choice of rapid-onset opioids for
management of BTcP
Factors to consider include individual patient characteristics, likelihood of adherence,
characteristics of BTP and formulation preferences
Relevant patient attributes include lack of physical dexterity or weakness as it may make
administration of oral transmucosal fentanyl citrate more difficult because it requires
active patient participation
The presence of xerostomia may make some oral medications more difficult to
administer
Mucositis may also influence the choice of an appropriate formulation, although most
formulations are well tolerated in this situation
Smith HS. J Pain Res. 2013;6:189-200.
Evidence-based recommendations from the EAPC on
use of opioids in BTcP
Recommendations for opioids in breakthrough pain
Strong recommendation that pain exacerbations from uncontrolled background pain
should be treated with additional doses of immediate-release oral opioids
Appropriate titration of around-the-clock opioid therapy should always precede
recourse to potent rescue opioid analgesics
BTcP can be effectively managed with oral, immediate-release opioids or buccal or
intranasal fentanyl preparations
In some cases buccal or intranasal fentanyl preparations are preferable to immediaterelease oral opioids because of more rapid onset of action and shorter duration of effect
Weak recommendation that immediate-release formulations of opioids with short halflives should be used to treat pre-emptive predictable episodes of BTcP in the 20–30 min
preceding the provoking manoeuvre
EAPC, European Association for Palliative Care
Caraceni A, et al. Lancet Oncol. 2012;13(2):e58-68.
ESMO: recommendations for BTcP
Immediate release oral morphine is appropriate to treat predictable episodes of BTP
(i.e. pain on moving, on swallowing, etc.) when administered at least 20 min before such
potential pain triggers (II A)
Intravenous opioids; buccal, sublingual and intranasal fentanyl drug delivery have a
shorter onset of analgesic activity in treating BTP episodes in respect to oral morphine
(I A)
Ripamonti I, et al. Ann Oncol. 2012;23 Suppl 7:vii139-54.
Comparative efficacy of fentanyl buccal tablet
t (min): mean PID (95% Crl)
Meta-analysis of 10 RCTs
INFS, FPNS, FBT, and OTFC showed greater relative
PIDs vs placebo than all other medications as early
as 15 minutes post-baseline
With exception of MSIR, all medications were more
efficacious vs placebo from 30 minutes postbaseline
IFNS, intranasal fentanyl spray; FPNS, fentanyl pectin nasal
spray; FST, fentanyl sublingual Tablets; FBSF, fentanyl buccal
soluble film; FBT, fentanyl buccal tablets; OTFC, oral
transmucosal fentanyl citrate; MSIR, morphine sulphate
immediate release
15: 1.68 (1.40; 1.96)
30: 1.95 (1.63; 2.27)
45: 1.95 (1.50; 2.39)
60: 1.94 (1.47; 2.41)
15: 0.56 (0.13; 0.99)
30: 1.13 (0.56; 1.69)
45: 1.30 (0.67; 1.92)
60: 1.55 (0.88; 2.21)
15: 0.53 (-0.03; 1.10)
30: 0.83 (0.21; 1.46)
45: 0.88 (0.40; 1.37)
60: 0.93 (0.19; 1.68)
15: 0.21 (-0.07; 0.48)
30: 0.61 (0.26; 0.96)
45: 0.71 (0.30; 1.12)
60: 0.90 (0.47; 1.33)
15: 0.51 (0.29; 0.73)
30: 0.96 (0.62; 1.30)
45: 1.41 (1.07; 1.76)
60: 1.68 (1.30; 2.05)
15: 0.46 (0.12; 0.81)
30: 1.01 (0.57; 1.44)
45: 1.32 (0.82; 1.82)
60: 1.52 (0.95; 2.09)
15: 0.12 (-0.35; 0.59)
30: 0.51 (-0.13; 1.16)
45: 0.83 (0.13; 1.53)
60: 1.02 (0.23; 1.81)
-3.0
INFS
FPNS
FST
FBSF
FBT
OTFC
MSIR
-2.0
Favours placebo
Zeppetella G, et al. J Pain Symptom Manage. 2014;47:772-85.
-1.0
0.0
PID
1.0
2.0
Favours treatment
3.0
Opioids are the ‘‘rescue medication” of choice in
management of BTcP
Dose titration scheme for opioid ‘‘rescue medication”
Starting dose of opioid
Pain controlled/
no adverse effects
Pain controlled/
adverse effects
Pain not controlled/
no adverse effects
Pain not controlled/
adverse effects
Continue current
dose opioid
Decrease
dose opioid
Increase
dose opioid
Change
treatment
The dose of opioid ‘‘rescue medication” should be determined by individual titration
Davies A, et al. Eur J Pain. 2009;13(4):331-8.
Adverse effects associated with opioids
Adverse events
Sedation
Dizziness
Nausea
Common
Vomiting
Constipation
Physical dependence
Tolerance
Respiratory depression
Delayed gastric emptying
Hyperalgesia
Less common
Immunologic dysfunction
Hormonal dysfunction
Muscle rigidity
Myoclonus
Benyamin R, et al. Pain Physician 2008;11:S105-S120.
Patients prefer an oral transmucosal route for relief
of BTcP
Responses to questions about potential use of different routes of administration
(‘‘would you consider using such a product?’’)
Oral transmucosal route
Intranasal route
Intrapulmonary route
Subcutaneous route
250
208
193
Number of patients
200
150
135 142
100
82
50
70
58
67
77 77
55
29
16
26 31
14
0
Yes
No
Multicentre European study of BTcP in 320 patients
Davies A, et al. Eur J Pain. 2011;15(7):756-63.
Possibly
Unfamiliar
with concept
Rapid-acting opioids are underused in management
of BTcP
Despite the availability
and utility of rapidly-acting
opioids
only
10%
of oncologists
identified this as a
recommendation they
would make
The limitations in pain-related knowledge and practice within the
oncology community have not been adequately addressed
Simon SM, Schwartzberg LS. J Opioid Manag. 2014;10(3):207-15.
Breuer B, et al. J Clin Oncol. 2011;29(36):4769-75.
Implementing guidelines for BTcP
Preparation
Step 1: Set up a team
Step 2: Evaluate current practices
Step 3: Set objectives
Step 4: Prepare the way for implementation
Step 5: Plan the implementation process
Step 6: Get feedback on the tools
Implementation
Step 7: Implement the plan
Evaluation
Step 8: Evaluate the progress
EONS. Breakthrough cancer pain guidelines 2013.
Available at: http://www.cancernurse.eu/documents/EONSBreakthroughCancerPainGuidelines.pdf. Accessed 13 Apr 2015.
The role of the nurse in treating BTcP
In the clinical and home-based settings, the nurse is one of the core professionals within
a multidisciplinary team who is well positioned to identify problems and plan care
accordingly
Oncology nurses have a key role to play in identifying, assessing, and managing BTcP,
which should be conducted for each patient on an individual basis
Frequent contact with patients allows nurses to observe patients and actively
communicate with them about their pain, potentially resulting in a more accurate
diagnosis, better management of BTcP, and improved patient satisfaction with treatment
EONS. Breakthrough cancer pain guidelines 2013.
Available at: http://www.cancernurse.eu/documents/EONSBreakthroughCancerPainGuidelines.pdf. Accessed 13 Apr 2015.
Nurses need adequate training to care for patients
with BTcP
100
90
77%
80
Nurses (%)
70
57%
60
50
38%
38%
40
30
20
10
0
Unaware that
medications
specifically intended
for treatment of BTCP
exist
Reported that oral
opioids were normally
prescribed for BTCP at
their workplace
Did not use nonpharmacological
treatments for BTCP
Recommended
positional change
Patients do not receive the appropriate medical treatment for BTcP: nurses need better
training about assessment and management of BTcP
Questionnaire-based survey of nurses (1241 completers) from 12 European countries who care for patients with cancer
Rustøen T, et al. Eur J Oncol Nurs. 2013;17(1):95-100.
Improving patient communication
Carers can play an active role in assessment and management of pain, but carer
managed analgesia requires good communication with the clinician
Clinicians and nursing staff should get to know the patient and family as well as possible
to enable patients and family to voice their fears, wishes and concerns with confidence
Patient input plays a major part in getting the most out of treatment: clinicians should
encourage patients to report intensity, quality, location and pattern of pain
Scottish Intercollegiate Guidelines Network. Control of pain in adults with cancer.
Available at: http://www.sign.ac.uk/pdf/SIGN106.pdf. Accessed 13 Mar 2015.
Key aspects of good communication
Good communication with patients and carers happens when:
– it is at their level of understanding
– is non-patronising
– free of jargon
– healthcare staff know the patient and carers well and actively listen
Poor communication between patients and professionals may result in clinical
assessment that is not comprehensive, and under-reporting of pain by patients
Scottish Intercollegiate Guidelines Network. Control of pain in adults with cancer.
Available at: http://www.sign.ac.uk/pdf/SIGN106.pdf. Accessed 13 Mar 2015.
Summary
BTcP can have many causes, and is experienced by about half of patients with cancer
BTcP has a negative impact on all aspects of quality of life
BTcP requires prompt diagnosis and treatment using defined algorithms
Opioids are the rescue medication of choice in management of BTcP
Improved communication with patients and among healthcare providers is essential in
improving management of BTcP