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Sebastiano Mercadante, MD
Professor of Palliative Medicine, University of Palermo
Director Anesthesia & ICU - Pain Relief & Palliative Care Unit
La Maddalena Cancer Center, Palermo – Italy
LE COMPONENTI DEL DOLORE
ONCOLOGICO
Dolore di base o persistente
BreakThrough cancer Pain (BTcP)
1-Portenoy RK, et al. Oxford Textbook of Palliative Medicine (3rd ed). Oxford: Oxford University Press; 2004:438-58
2-Bennett D, et al. Pharmacy & Therapeutics. 2005;30:354-61.
3-Zeppetella G. et al. Curr Op Supp Pall Care
Realizzato con il
contributo non
condizionato di Cephalon
Characteristics of BP
•
•
•
•
•
•
•
Frequency 30-90%
Moderate to severe intensity
Rapid onset (<3 minutes in 43% of patients)
Often unpredictable
Relatively short duration (30-60’)
Frequency: 1-4 episodes per day
Features:
Physical consequences
Psychological consequences
Social consequences
Resource consequences
Episodic (Breakthrough) Pain
Consensus Conference of an Expert Working Group of the EAPC, Cancer 2002
Sebastiano Mercadante, M.D.1
Lukas Radbruch, M.D.2
Augusto Caraceni, M.D.3
Nathan Cherny, M.D.4
Stein Kaasa, M.D., Ph.D.5
Friedemann Nauck, M.D.6
Carla Ripamonti, M.D.3
Franco De Conno, M.D.3
the Steering Committee of the
European Association for Palliative
Care (EAPC) Research Network
BACKGROUND: Breakthrough pain is transitory exacerbation of pain that occurs
in addition to otherwise stable persistent pain. The wide differences in
estimation of incidence reported in literature are probably because of different
settings and meanings attributed to the definition to breakthrough pain.
METHODS: A panel of experts met to establish the actual knowledge on
breakthrough pain, according to the evidence in literature and experience. They
agreed that episodic or transient pain could be a more simple and adequate term
in most languages, including English, France, Italian, and Spanish.
RESULTS: A specific assessment and precise pain characterization are essential to
plan the most appropriate treatments. Despite the relevance of this temporal
pain pattern for the influence on the outcome and quality of life, few controlled
studies have been performed to give evidence of a specific approach. Several
experiences have reported the possible efficacy of different drugs, route of
administration, and modalities of administration in different circumstances.
CONCLUSIONS: Prospective studies with previous treatments using similar
terminologies are necessary to find the most convenient therapeutic
intervention, according to the temporal pattern characteristics and the pain
mechanism involved.
Cancer 2002;94:832-9. © 2002 American Cancer Society.
DOI 10.1002/cncr.10249
KEYWORDS: cancer pain, breakthough pain, incident pain, transient pain,
opioids, nonsteroidal antiinflammatory drugs (NSAIDs), pamidronate,
transmucosal fentanyl, radiotherapy, spinal opioids.
Breakthrough pain… stories
Prima definizione:
“BTcP is a transitory increase in pain to greater than moderate intensity
which occurs on a baseline pain of moderate intensity or less
(Portenoy and Hagen, 1990).
4
7
?
Pain intensity should be severe (on a numerical scale 7/10), but the baseline
pain could be moderate (on a numerical scale 4-6/10) (Serlin et al., 1995). Thus,
the differences between the intensity of BTcP could be minimal (1-2 points on a
numerical scale).
ca Aielli, MD #, Fabrizio David, MD*, Teresa Gammucci, MD^, Filomena Narducci, MD^ , Gaetano Lanzetta, MD @, Rossella Restuccia, MD @, Alessan
♦ Mercadante S et al. Breakthrough pain in oncology: a
longitudinal study.
J Pain Symptom Manage 2010.
♦ Mercadante S. et al. Breakthrough pain in advanced
cancer patients followed at home: a longitudinal study.
J Pain Symptom Manage 2009
♦ Mercadante S. et al. Attitudes on breakthrough pain
in hospice. An Italian survey.
Supportive Care Cancer 2010
Pts admitted in APRPC were divided in the following
classes, according to the level of background pain
intensity and analgesic drugs used at admission (T0):
a. Patients with no pain-mild pain NO opioids
b. Patients with mild pain receiving weak opioids
c. Patients with moderate pain receiving weak opioids
d. Patients with severe pain receiving weak opioids
e. Patients with mild pain receiving strong opioids
f. Patients with moderate pain receiving strong
opioids
g. Patients with severe pain receiving strong opioids
h. Patients with severe pain, receiving NO opioids
i. Patients with moderate pain, receiving NO opioids.
MEANINGFUL CUT-OFF PAIN INTENSITY FOR BTcP
CHANGES IN ADVANCED CANCER PATIENTS. Submitted
The meaningful pain intensity for asking for a BTcP
medication was 7.1/10. 77% of patients had a pain
intensity of 7-8 on a numerical scale 0-10.
The meaningful pain intensity for adequate analgesia
after a BTcP medication was 3.5/10. Similarly, 77% of
patients had a pain intensity of 3-4.
There was no relationship with the variables examined
for coping. Concerns about the use of BTcP medications
were minimal.
Dolore osseo: prognosi

Per la sua natura intermittente, il dolore è difficile da
controllare, e limita il malato ad evitare di muovere con
ovvie conseguenze sulla qualità di vita.
Il dolore incidente associato a metastasi ossee è
considerato un fattore prognostico negativo per il
controllo del dolore (Bruera et al,1989, Mercadante et
al,1992).
 La libertà di movimento è particolarmente difficile da
raggiungere (Banning et al,1991).

Construct for opioid titration in
incident pain
Analgesic line
Toxicity line
Dose
Dose for pain on movement
Dose for pain at rest
Effects
Mercadante S et al. Optimization of opioid therapy……J Pain Symptoms Manage 2004
Balancing Analgesia and Side Effects
Ideal Breakthrough Pain
Medication
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•
•
•
•
Rapid onset
Short duration of effect
Minimal side effects
Noninvasive, easy-to-use
Cost-effective
Portenoy RK, Hagen NA. Pain. 1990;41:273-281.
BTP Profile
Pain Intensity
Pain relief gap
Oral Morphine Profile
BTP Profile
5
Overmedication
30
60
Time (minutes)
Short-acting opioids are the mainstay
of pharmacological treatment1
Due to its nature, breakthrough cancer pain requires a treatment that:
Has a fast onset of action2
Is appropriate in its potency3
Is easily administered3
The WHO analgesic ladder recommends background pain is controlled
with around-the-clock analgesia4
Issues with opioids:1
Only effective if breakthrough cancer pain is an opioid-responsive
pain1
Only effective if onset of action reflects the duration of the episode1
1. Davies AN. Brit J Hosp Med 2006; 67: 414. 2. Mercadante S et al. J Pain Symptom Manage 2004; 27:
352-359. 3. Mercadante S et al. Cancer 2002; 94: 832-839. 4. World Health Organisation. WHO analgesic
ladder for cancer. www.who.int/cancer/palliative/painladder/en/index.html. Accessed 09/06/07.
TRATTAMENTO DEL BTcP
• Il trattamento ideale dovrebbe coprire tutta la variabilità degli
episodi di BTcP
Durata
Durata
Durata
Intensità
Durata
Dolore persistente trattato con terapia
oppioide
Tempo
3’
60’
19
Flexible use of oral morphine
• Anticipated before starting activity
(approximately 30’ before)
• Patients happy with… one shot…
• Slow onset BP
Main data of new formulation
- Efficacy in acute administration in comparison with
placebo or oral drugs.
- Efficacy in long-term studies
- Pain relief within 7-15 min.
- Dose-proportionality
- Uncertainty on dosing (to titrate..?)
BTcP Therapies: Delivery Systems
MERCADANTE, DRUGS 2012
1998
Oral trans
-mucosal
fentanyl
citrate
OTFC
2006/2008
FENTORA®(US)/
EFFENTORA™(EU)
Oral
Transmucosal Effervescent Buccal
Tablet
Lozenge
2009
ONSOLIS™
(US) FBSF
Fentanyl Buccal
Soluble Film
2008
Rapinyl™/
Abstral
(EU) SLF
Sublingual
Fentanyl
2009
2009
®
Instanyl™ NasalFent
(EU) FPNS
(EU) INFS
Intranasal
Fentayl Pectin
Fentanyl Sprayy Nasal Spray
BTcP Therapies: Early Absorption parameters
Actiq
Effentora
Onsolis
Abstral
Dose
(mcg)
400
100-1600
400
100-800
400
100-1200
400
100-800
Dwell Time
(min)
15
15-20
Cmax
(ng/mL)
0.6
0.9
0.7
Tmax
(min)
120
(30–240)
45
(20–240)
60
-
Instanyl Nasalfent
400
50-200
400
100-800
N/A
N/A
0.7
2.5
1.5
(23–240)
15
(6-90)
20
(5-90)
Pts should be assessed for the presence of BtcP – D
Pts with BtcP should have this pain specifically assessed – D
The management of BtcP should be individualized – D
Consideration should be given to treatmetn of the underlying cause of pain – D
Consideration should be given to avoidance of the precipitating factors – D
Consideration shoulc be given to modification of the background analgesia - D
Opioids are the rescue medication pf choice – D
The dose should be determined by individual titration – B
Non pharmacological methods may be useful – D
Non-opioid analgesics may be useful – D
Interventional techniques may be useful – D
Pts should have BtcP re-assessed - D
Respiratory function during parenteral opioid titration
for cancer pain
Estfan et al, Palliat Med 2007
Pain score
Opioid dose
Before titration
6.8
73
Pain control
1.9
169
Dose of breakthrough oral opioid versus ATC dose from
the four studies of OTFC
Significant relationship (p<0.001)
High variability
120
100
100
80
60
40
20
0
0
100
200
300
400
500
600
700
800
Hagen et al. J Palliat Med 2007
Zeppetella J. Opioids for cancer breakthrough pain: a pilot
study reporting patient assessment of time to meaningful
pain relief. JPSM 2008
• 50 pts
• 250 episodes
• The dose of the oral rescue dose was on average 18%
of the ATC dose
• For OTFC, the rescue dose was approximately 36% of
the ATC dose
Efficacy and safety of IV bolus of morphine for
episodic (breakthrough) pain.
Mercadante et al, JPSM, 2004
Intravenuos morphine for breakthrough pain in
an acute pallliative care unit: a confirmatory
study.
Mercadante et al JPSM 2008
OTFC versus IV-morphine for breakthrough pain.
Mercadante et al, Br J Cancer 2007
DOSING FENTANYL BUCCAL TABLET FOR BREAKTHROUGH CANCER
PAIN: DOSE TITRATION VERSUS PROPORTIONAL DOSES.
Mercadante et al, CMRO 2012
126 mg di equivalenti di morfina (range 60-480 mg) per il
dolore di base.
293 episodi di BTcP trattati con P e T.
La necessità di ricorrere ad ulteriori dosi è stata maggiore nel
gruppo T per il primo episodio (P< 0.0005). In pazienti che
ricevevano dosi di morfina >120 mg/die, un numero
significativo di pazienti ottenne una riduzione del dolore
>50% nel gruppo P rispetto al gruppo T (p=0.040).
Nessuna differenza di effetti collaterali
86%
9
8,4
84%
8
75%
7,3
7
6
T0
T15
>33%
>50%
5
3,7
4
35%
2,8
3
2
1
0
Propor onal
Titra on
Pain intensity differences between the two groups for episodes of BTcP in patients receiving
doses of oral morphine equivalents ≥120 mg/day (60 and 60 episodes in group P and T,
respectively)
No differences in adverse effect intensity
Percentage of pts with adverse effects with an intensity of 1-2 on a 0-3 scale.
No patient had intensity of 3
Conclusione
Il BTcP di tipo incidente al movimento richiede un’ accurata
valutazione sulle caratteristiche temporali di latenza e durata e
persistenza dello stimolo, che si presentano in maniera molto
diversa.
 Particolare attenzione dovrà essere posta sulle possibilità di
trattamento delle metastasi ossee
 Dovranno essere considerati anche obiettivi realistici rispetto alle
capacità di movimento ed alla prognosi.
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
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In base a tali caratteristiche si sceglierà il potenziamento dell’
analgesia di base con i mezzi farmacologici disponibili, e il farmaco
al bisogno da utilizzare.
Considerata l’ eterogeneità del BTcP, si dovrà personalizzare il
trattamento
Breakthrough pain in elderly
 No studies performed with the primary
outcome of comparing adults and old
patients.
Experience provide infomation that that
opioid tolerant patients can be treated with
proportional doses safely.
 Perception of less tendency to call for
BTcP events
 Studies ongoing
Sebastiano Mercadante