1. BeCOn OWN Educational Program
Modules

2. Breakthrough cancer pain (BTcP)
Module 4
Breakthrough cancer pain (BTcP)
Date of preparation: June 2015 HQ/EFF/15/0024c

3. Contents
Overview of BTcP
Management of BTcP

4. Overview of BTcP

5. 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.

6. 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.

7. 39.9% in outpatient clinics
Prevalence of BTcP
39.9% in outpatient clinics
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%)
More than one in two patients with cancer pain also experiences BTcP
80.5% in hospice
Deandrea S, et al. J Pain Symptom Manage. 2014;47(1):57-76.

8. 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.

9. Characteristics of BTcP
Median number of BTcP episodes
Median duration
Characteristics of BTcP
3 per day
Median time to peak intensity
60 min
10 min
Multicentre European study of BTcP in 320 patients
Davies A, et al. J Pain Symptom Manage. 2013;46(5):

10. BTcP has many causes
BTcP is related to different causes
BTcP is not a single entity, but a spectrum of very different entities
Treatment-related
(e.g. radiation induced injury, chemotherapy, surgery)
Cancer-related
(e.g. inflammatory response, nerve compression)
Concomitant illness
Davies A, et al. Eur J Pain. 2009;13(4):331-8.

11. BTcP has complex pathophysiology
BTcP has different pathophysiologies
BTcP has complex pathophysiology
Nociceptive
Mixed
Neuropathic
Davies A, et al. Eur J Pain. 2009;13(4):331-8.

12. The onset of BTcP is rapid, but variable
Time to peak intensity of BTcP
Median time to peak intensity is 10 minutes
Number of patients (n= 936)
100
500
250
300
150 50
All BTcP
Spontaneous BTcP
Incident BTcP
400
0-5 min
6-10
min
11-15 min
16-20 min
21-25 min
26-30 min
31-40 min
41-50 min
>60 min
461
159
234
111 74 48 44 39 24 40 14
131 62 51 13 3 10 2 72 34 27
450
350
200
51-60 min 31
Study of 1000 cancer patients from 13 European countries
Davies A, et al. J Pain Symptom Manage. 2013;46(5):

13. The duration of BTcP is extremely heterogeneous
Duration of untreated episodes
The median duration for all BTcP was 60 min (range <1 min to 360 min)
All BTcP
Spontaneous BTcP
Incident BTcP
140
120
115
100 87 80 77 73
Number of patients (n= 505) 68 63 63 60 50 46 40 37 33 31 33 29 28 23 18 19 20 14 13 8 6
In this study by Davies et al cancer patients from 13 European countries were screened for breakthrough pain using a recommended diagnostic algorithm and then questioned about the characteristics and management of their pain. This slide shows the duration of untreated episodes of BTcP. While there was broad variability, ranging from <1 minute to 360 minutes, the median duration was 60 minutes. 4 5
0-10 min
11-20
min
21-30 min
31-60 min
61-90 min
min
min
min
>180 min
Study of 1000 cancer patients from 13 European countries
Davies A, et al. J Pain Symptom Manage. 2013;46(5):

14. 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):

15. 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 1 2 3 4 5 6 7 8 9 10
Numerical rating (0-10)
Study of 1000 cancer patients from 13 European countries.
Davies A, et al. J Pain Symptom Manage. 2013;46(5):

16. BTcP has widespread implications
Depression
Walking
Working
Activities
BTcP
Increases
Reduces
Affects
Anxiety
Healthcare costs
Social relationship
Sleep
Quality of life
Satisfaction with therapy
EONS. Breakthrough cancer pain guidelines Available at: Accessed 13 Apr 2015.

17. Management of BTcP

18. General considerations on management of breakthrough pain
The aim of breakthrough pain management is to reduce the intensity, severity, and impact of pain
General considerations on management of breakthrough pain
Successful management is best achieved by thorough assessment, good communication, reassurance about pain relief and encouraging patient and carer participation
Management involves:
general assessment (e.g. pain assessment, explanation)
lifestyle changes (e.g. coping strategies)
management of reversible causes (e.g. incident pain precipitants)
modification of the pathological processes (e.g. antineoplastic therapies)
symptomatic management of BTcP (e.g. pharmacological and non-pharmacological)
reassessment (e.g. evaluation of pain and management)
Zeppetella G. Curr Opin Support Palliat Care. 2009;3(1):1-6.

19. Non-pharmacological methods for management of breakthrough pain
However, there is relatively little evidence to support the use of these interventions in the treatment of breakthrough pain episodes
A variety of non-pharmacological methods are used by patients, including:
Rubbing/massage
Application of heat
Application of cold
Distraction techniques
Relaxation techniques
Davies A, et al. Eur J Pain. 2009;13(4):331-8.

20. 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
Patient does not have breakthrough pain, but does have uncontrolled background pain NO NO
YES NO
Does the patient have transient exacerbations of pain?
PATIENT DOES NOT HAVE BREAKTHROUGH PAIN
YES
PATIENT HAS BREAKTHROUGH PAIN
Davies A, et al. Eur J Pain. 2009;13(4):331-8.

21. 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
Asking key questions can provide important insights into the patient’s pain
Onset of pain?
Frequency of pain?
Site of pain?
Radiation of pain
Quality (character) of pain?
Intensity (severity) of pain?
Duration of pain?
Exacerbating factors?
Relieving factors?
Response to analgesics?
Response to other interventions?
Associated symptoms?
Interference with activities of daily living?
Davies A, et al. Eur J Pain. 2009;13(4):331-8.

22. The Breakthrough Pain Assessment Tool (BAT)
A fully validated clinical assessment tool for breakthrough pain in cancer patients
The BAT can facilitate the management of patients with breakthrough cancer pain in a clinical setting
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
Webber K, et al. J Pain Symptom Manage. 2014;48(4):

23. 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 European Oncology Nursing Society. Available at: Accessed 12 Mar 2015.

24. APM Recommendations
Patients with pain should be assessed for the presence of breakthrough pain (grade of recommendation: D)
Patients with breakthrough pain should have this pain specifically assessed (D)
The management of breakthrough pain should be individualised (D)
Consideration should be given to treatment of the underlying cause of the pain (D)
Consideration should be given to avoidance / treatment of the precipitating factors of the pain (D)
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.

25. APM Recommendations
Opioids are the “rescue medication” of choice in the management of breakthrough pain episodes (D)
The dose of opioid “rescue medication” should be determined by individual titration (B)
Non-opioid analgesics may be useful in the management of breakthrough pain episodes (D)
Non-pharmacological methods may be useful in the management of breakthrough pain episodes (D)
Interventional techniques may be useful in the management of breakthrough pain (D)
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.

26. 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 European Oncology Nursing Society. Available at: Accessed 12 Mar 2015.

27. Characteristics of immediate-release opioids used in BTcP
Onset of
analgesia
Duration
of effect
Advantages (A)/Disadvantages (D)
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
Same as morphine
Hydromorphone (oral)
D - no liquid concentrate, slow onset of analgesia for idiopathic BTP
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
Hydrophilic
This slide shows the characteristics of short-acting opioids used for treatment of BTcP. Because the time from onset to peak pain intensity of BTP is generally only a few minutes and the average duration is one-half hour, the opioid that is used to manage most cases of BTcP should have a rapid onset of effective analgesia and a duration of action appropriate for the characteristics of the BTcP. Morphine, hydromorphone, and oxycodone are the oral opioids most often used to treat BTP when they are administered in their immediate release formulations of tablets, capsules, or liquid concentrates. Because of its highly vascular nature, the oral cavity is also used as a site for local rapid absorption of opioids.
Lipophilic
Bennett D, et al. P&T. 2005;30:

28. 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 30 60 90
120
150
180
210
240
270
Time (min)
A slow onset of action (analgesia: min; peak analgesia: 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,

29. Treatment strategies for BTcP
12 am
Pain or analgesic intensity 10 8 6 4 9 7 5 3 1 2
3 am
6 am
9 am
12 pm
3 pm
6 pm
9 pm
ATC ER Opioid Alone
BTcP has a time profile that is different from that of chronic persistent pain and should therefore be managed differently
Treatment of BTcP with oral immediate release opioids can take minutes to produce an analgesic effect, which lasts for 3-6 hours
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
12 am
Pain or analgesic intensity 10 8 6 4 9 7 5 3 1 2
3 am
6 am
9 am
12 pm
3 pm
6 pm
9 pm
ATC ER Opioid + IR Opioid
12 am
Pain or analgesic intensity 10 8 6 4 9 7 5 3 1 2
3 am
6 am
9 am
12 pm
3 pm
6 pm
9 pm
ATC ER Opioid + ROO
Simon SM, Schwartzberg LS. J Opioid Manag. 2014;10(3):

30. Currently available rapid-onset opioid formulations
NASAL SPRAY
BUCCAL
Lozenge
Effervescent tablet
Film
SUBLINGUAL
Tablet
Effervescent tablet
Spray*
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):

31. 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:

32. 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 immediate- release oral opioids because of more rapid onset of action and shorter duration of effect
Weak recommendation that immediate-release formulations of opioids with short half- lives 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.

33. 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:vii

34. Comparative efficacy of fentanyl buccal tablet
t (min): mean PID (95% Crl)
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)
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 post- baseline
INFS
FPNS
FST
FBSF
FBT
INFS, fentanyl pectin nasal spray, fentanyl buccal tablet, and oral transmucosal fentanyl citrate showed greater PIDs relative to placebo than other BTCP medications 15 minutes after intake. All other medications showed greater PIDs relative to placebo at 30 minutes, except morphine sulfate immediate release, which did not show efficacy over placebo until 45 minutes. Only INFS produced clinically meaningful pain relief (absolute PID ≥2) at 15 minutes.
OTFC
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
MSIR
-3.0
-2.0
-1.0
0.0
1.0
2.0
3.0
PID
Favours placebo
Favours treatment
Zeppetella G, et al. J Pain Symptom Manage. 2014;47:

35. Opioids are the ‘‘rescue medication” of choice in management of BTcP
Dose titration scheme for opioid ‘‘rescue medication”
The dose of opioid ‘‘rescue medication” should be determined by individual titration
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
Davies A, et al. Eur J Pain. 2009;13(4):331-8.

36. Adverse effects associated with opioids
Adverse events
Common
Sedation
Dizziness
Nausea
Vomiting
Constipation
Physical dependence
Tolerance
Respiratory depression
Less common
Delayed gastric emptying
Hyperalgesia
Immunologic dysfunction
Hormonal dysfunction
Muscle rigidity
Myoclonus
Benyamin R, et al. Pain Physician 2008;11:S105-S120.

37. 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
200
142
150
135
Number of patients
100 82 77 77 70 67 58 55 50 29 26 31 16 14
Yes No
Possibly
Unfamiliar with concept
Multicentre European study of BTcP in 320 patients
Davies A, et al. Eur J Pain. 2011;15(7):

38. Rapid-acting opioids are underused in management of BTcP
only 10%
Despite the availability and utility of rapidly-acting opioids
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):
Breuer B, et al. J Clin Oncol. 2011;29(36):

39. 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 Available at: Accessed 13 Apr 2015.

40. 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 Available at: Accessed 13 Apr 2015.

41. Nurses need adequate training to care for patients with BTcP
Patients do not receive the appropriate medical treatment for BTcP: nurses need better training about assessment and management of BTcP
100 90
77% 80 70
57% 60
Nurses (%) 50
38%
38% 40 30 20 10
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 non-pharmacological treatments for BTCP
Recommended positional change
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):

42. Improving patient communication
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
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
Scottish Intercollegiate Guidelines Network. Control of pain in adults with cancer. Available at: Accessed 13 Mar 2015.

43. 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: Accessed 13 Mar 2015.

44. 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