. π υ - α

α υ

α πα (BTcP):

π υ α α;

Γ : • α Ν • α α υ BTcP • υ α • π π •

:

• Θ απ υ α π • Φ α α ω (rescue medications) • α υ υ Ν υ

Ό π υ α α α π υ π υ υ απ

υ υ υ υ α α α α α π

α α π υ

α Montreal

IASP 2010

84 250

α π π Γα α Ρ99 α α Ρ10

υ . α / π

Η Δ π αΕ υ α υ υ Σ90 α

α π υ α υ υ

απα α π π α

α π υ π υ υ α πα α

΄84:

΄89: ΄02: ΄09:

α:

1. Review of Prevalence, characteristics and managemend of

BTcP: 38 α Mischra Σ09 2. EPCRC: 51 α Ρ11

α π φ Breakthrough Cancer Pain (BTcP)

π π α π αφ υ (Postenoy, Hagen) ΟepisodicΠ, ΟtransientΠ (EAPC task force) απ υ υ breakthrough (πα υ ) α απ φ (Hagen, Davis

Mercadante)

BTcP: α 1,2

α πα υ π υ π υ φα α αυ α α, α π π π α, πα

α π α α υ υπ π (BP)*

΄89 Portenoy: ΄02 Svenden Swandic

α:

Ρ14 α α 1:

Δ α Ε, Δ πα υ Ε BP αφ Δ υ υΕ Δ υ υΕ BP

Δπ π : α π , α υ υπ υ π υ π α α Ε α π υ BP7NRS

αφ BTcP-BP>3NRS

*BP: background pain 1. BTcP: a synthesis of taxonomy, pathogenesis,

therapy and good clinical parctice in Italy

F. Zucco, Adv.Ther., 2014

BTcP:

α: π πα (65%-76%) Ν απ α (10%-20%) Ν α Ν Ν υ πα Ν α

υχ α: 19%-95% α πα 1

φ α

υ υπ 2

α 3 ( . α (-30%) vs α Φ)

2

α υ 4

α α υ 5

υ υ α α α 6

1 Zeppetella, Ribeiro Ρ03, Zeppetella Ρ11 2 Caraceni et al: Pain prevalence in a population of cancer patients (QYDEI) J. Pain Sympt Manage

2012

3 Mercadante Ρ02, Greco Σ11, Margarit Ρ12 (Eur. J. Pain) 4 Caraceni et al Ρ99 5 Bruera et al Σ99 6 Saini A: A Circadian variation of BTcP Eur J.Pain 2012

χ : π π α π : π π Ν υ α π Ν 1 , 123

α , 47 , 76 π α α α: ECOG-PS, VAS, POS, QUDEI (Italian version of BPQ), BTcP

diary

π α α: 60% π υ α υ α 10π Ν 6 ( :9:45, π α 10:30)

α α α: υ φ α π . π 1

ς φ υα α π Φ -Φ π υ α α π π

1σaberet et al Ρ81 Yoshida Ρ06

Asai Ρ07

Circadian variation of BTcP A. Saini et al. Eur.J.Pain, May 2012

Prevalence of BTcP (controlled - uncontrolled) background pain in the Cancer population

A. Davis, Full publication planned for 2014

π : α α υ α υ BTcP υ π υ α , α α α υ α α υ

Η υ α υ χ α

• π υ • α α α α α α α , α π • Χ profil • Έ α : α 4% α 34% υ 62% • π : 3/

• α 38%-53%

• υ πα 10%-54% • 20%-52%

• π α 29% • α 45%

Davis et al2013

Eur J Pain

Mischra et al 2009

Zeppetella, Ribeiro

2003

2009

BTcP: χα α - α

2 α

υ α , αυ , πα (spontaneous, idiopathic)

Davis et al, 2013

υ α 41,5% α 10Σ

α 60Σ

, π α (incident)

υ α 44% α 5Σ

α 45Σ

Δα Ε BTcP

Δ Ε BTcP

(volitional) (non volitional)

Θ απ υ ς πα α ς (procedural)

A

BTcP: α

• 17%-30%: υ α • απ π υπ π υ BTcP

( υ )1

• Δ Ε α α π 2

1 EPCRC Ρ11 2 εercadante Ρ11

Δ - απ υχ α Ε π

α χ υ υπ υ π υ (Οend of doseΠ failure pain)

• αφ πα χα α υ υπ π υ BTcP

1. υ α α απ π υ υ

2. φ υα π Ν π (α υ α Ν υπ α α)

3. υα π (αφ π Δ π υπ Ν C Ν π α )

4. π υ . υ . υ α ( )

• (incident):

• υ (spontaneous):

1 & 2

π υ υ 3 & 4

α α φ υ υ

BTcP: χα - πα α

α Ά

α *

ADL

α α

π

π π

α

α α π απ Θ απ α

* + BTcP: 12.000 $ / / - BTcP: 2.400 $ / /

αυ

BTcP

BTcP: π π

αφ α: • Webber V. et al: BTcP, a qualitative study involving patients with advanced cancer

Supp. Care Cancer 2011

• Davis et al: Multi- center Eur Study of BTcP Eur J Pain 2013

• Rutsoen et al: how nurses assess BTcP and the impact of this painΖ, an Eur. Survey Eur. J. Nurs. Onc 2012

• Fortner et al: A survey of pain related hospitalization J. Pain Sympt. Manage, 2003

• Abenethy AP: A health economic model of BTcP Am J Man Care, 2008

• Breivic H et al: Cancer related Pain: a pan Eur survey of prevalence, treatment and patient altitude

Ann Onc, 2009

• Current and historical ratio tablets: www.xe.com/currentlytablets2013

• Meriggi et al: BTcP: where we are; Rev on Clin Trials, 2013

π π ( υ χ α)

13 υ πα 28 υ & Φ 1.000 α

α α:

υ π α α:

α α Ρ09 α Ρ09

ADL (activities of daily life)

53% α α Θ α BTcP 19% α α α α α

αφ α α απ α 65.5%

10.5%

23.5% α α ADL

81% α π α α 11% α α π α 7% π α

: α π α ADL υ : α π α α π αφ α α υπ π BTcP1

1 Deadrea, Corlio, Commendary on Davis, 2013

Davis et al 2013: π υ Eur J Pain

Bedard et al 2013

MONO TO 33% α Φ α (rescue medication) α BTcP

• Ό π α υ α π 33% • Φ α 23% • π α 17% • Φ 12% • α α υφ α 10% • α α Φ 8% • Φ πα 7% • Γ α / υ υ α 2%

A survey of Canadian Cancer patients, perspectives on the characeristics and treatment of BTcP

Supp. Care Cancer

:

BTcP υπ απ α

Ν ( αφ )

ωπ π απ α

• υπ π • α φ π

πα

αφ

BTcP: α α π

• υπ π (survivors)

Alberta BTcP assessment tool (Delfi project validated, υ ) BPQ (Breef pain quest.) 2009

QUDEI (Italian Quest. for intense episodic Pain) 2012

Episodic Pain Doc Sheet (1 Hospice, Zeppetella)

BTP assessment tool (validated, A. Davis oral presentation) 2013

• Ν α • 2009 ( Ν αφ

απ BP) • α α BTcP

10 α α (tools) 7 υπ

BTcP : ω -

• α π υ π υ α profil υ

BTcP

• υ α π • π α

:

BTcP : απ υ α π

• α π υ • α α α α • π π πα α α α • φα α υ α π ( υ υπ Ν υ π α

απ )

• Φα α υ α π

• α α

Φ α α ω (Rescue medications)

υ Φ α α

BTcP : απ υ α π

φ * υ *

φ α (1 )

* α α α α PO (per os): απ α

Η

π α α (PO) (Short Acting Opioids: SAO)

π α α Έ α (Rapid Onset Opioids: ROO)

. α α (IV,SC) φ (IR) . α α Φα α

(Fast Fentanyls:FF)

- α -

OTFC (Actiq)*

SLF (Abstral)*

FBT (Effentora)

SLFS (Subsys)

FBSF (Breacyl)

INFS (Instanyl)*

FPNS (Pecfent)

BTcP : φ α α ω

• FC inhaler ( φ ) • FNS cytosan, FNS cytosan Ν poloxamer • SL υ φ • SL α • S φ • S α •

BTcP : φ α α ω υπ

υπ υ απ α υ απ α α α υ

BTcP, πα α π α α α, α υ α ,

(Rescue Dose), α π α υ υπ υ, α π υ

( α RD:1/6 24 υ α π )

EBM reviews

BTcP : π αχ α (PO): SAO

α χ α π (IV, SC) • φ • Θ α Δφ α α αφ Ε ( α ROO) • φ IV,SC RD: 15% -20% 24

εercadante et al Σ04 IV φ > FF α 30Σ IV φ = FF α 60Σ • IV φ + PCA: χ α Σ , Mercadante Ρ07 PCA : α α υ υ

Jamagushi Σ13

BTcP : π αχ α Έ α : ROO

Mercadante et al ‘07

H. Smith, A comprehensive review of ROO for BTcP CNS Drugs, 2012

BTcP : υ α α α α Φα α

( α – ), Fast Fentanyls

H. Smith, A comprehensive

review of ROO for BTcP CNS Drugs,

2012

BTcP : Φα α profil ω FF

α υ α υ • υ α α α π π υ α α (OTFC) • υ α α α Ν α • π • α • πα υ

α υ υ • υ α α π αυ α - - α • α α • α απ Φ (INFC) • πα υ • α Ν υ α • φ υ α

π α

π

α

BTcP : χ FF

• Φ α α • α α BTcP • α α ( α ) • α αυ α , π υ α α α • α ( υ α ) • α • πα υ (42% π π )* • α α •

* Corli C., OIPC, res. group, 2011

BTcP : π - υ α

α

IV,SC

Farrar et al Ρ98 Coluzzi et al Ρ01 (OTFC vs MS IR) Mercadante et al Ρ07 Shaiova Ρ04 (mucosities) Rayne et al Σ01 Taylor et al Ρ07 (QOL-non-cancer)

OTFC Portenoy Ρ06 Portenoy Ρ07 (Low back pain) Simpson Ρ07 (Neur Pain) Slatkin Ρ07 Farrar Ρ10 (non-cancer) Ashburn Ρ11 (vs Oxydone IR)

FBT

Rauck Ρ10 Diaz del Consuelo Ρ07

FBSF

Rauck Ρ09 Lennernas Ρ10 Nalamatzu Σ11 (QOL, DAPOS, PGEM: 6 )1

Uberall Ρ11 (PRD, HADS)1

( α: 12 )

SLF

1. DAPOS: Depression, Anxiety and positive outlook scale

PGEM: PatientΣs global evaluation of medication PRD: Pain related disability

HADS: Hamilton Anxiety, Depression Scale

π υ υ α FF

Kress Ρ09 Cristrup Σ08 (INFS vs Fent iv) Foster Ρ08 Mercadante Ρ09 (INFS vs OTFC) Kaasa Ρ10 (FF vs MSIR) Vissers Ρ10 (INFS vs OTFC, FBT, MSIR):

α υ Mercadante Ρ14 (INFS vs FPNS) Konsgaard Ρ14 (QOL) Thrones Ρ14 (400 INFS) Plock Ρ13 (400 INFS) Nave Ρ09 (cold, rhinitis, ozymetazoline) Nolte Ρ09 ( , π α ) Jacobsen Ρ10 (π α ) Registry studies 5 υ . : α off-label (overdose, abuse, misuse, diversion)

Ruggers Ρ13 ( / φ ) Vissers Ρ11 (INFS vs OTFC QALYs: quality adjust life years

INFS Portenoy Ρ10 Taylor Ρ10 Davis Ρ11 (FPNS vs MSIR

FPNS

Parikh N. Ρ13 Rauck R. Ρ12

FSLS

π υ υ α FF

Streisand ‘λ1 Egan ‘ίί

όarrar ‘λκ Coluzzi ‘ί1*** Mercadante ‘ίι****

Shaiova ‘ί4 (mucositis)

Taylor ‘ίι (non cancer)

----------------

----------------

Lennernas ‘λκ

Lenernas ‘1ί Rauck ‘ίλ

Rauck ‘ίλ

σalamatsu ‘11 Uberall ‘11

-----------------

-----------------

όoster ‘ί1 Kaasa ‘1ί

Kress ‘ίλ

Mercadante ‘ίλ

Mercadante ‘ίλ

Mercadante ‘ίλ* Vissers ‘1ί**

Vissers ‘11* QALYs

Φε

Κζδθδεά Απο εζε ηα- δεσ β α

Α φΪζεδα - Αθεε δεσ β α

Ιεαθοποέβ β απσ γελαπεέα

Συγελδ δεΫμ

Κσ ομ ή Ώφεζομ

*Mercadante ’ίλ INFS vs OTFC **Vissers ’1ί Ϋηηε β τγελδ β ωθ FF ***Coluzzi ‘ί1 OTFC vs MSJR (PO) ****Mercadante ‘ίι OTFC vs M(IV)

OTFC

5

5

3

SLF

5

5

INFS

5

3

OTFC SLF INFS Jadad score

• Fentanyl transmucosal, Towycross R. et al J. Pain Management, 1012

• Opioids for the management of BTcP, G Zeppetella, A. Davis

Cochrane database syst. Review, 2013

EBM: evidence based medicine

Fast Fentanyls: EBM reviews

4 RCTs 393 α OTFC 15 RCTs 1699 α 7 αφ FF (5 α , 2 ) 8 RCTs FF vs Placebo

4 RCTs FF vs π 1 RCT φ υ 2 RCTs π

2006 2013

*Έ π α : Jadad scoring system Σ96 χ : α α απ α α ROO

α απ π α α π

Opioids for the management of BTcP: systemic Review Zeppetella G, Davis A. Cochrane Library 2013

• α FFs α φ IV υ α α υ BTcP

• Ό α α ROO υπ υ υ Placebo • υ α α NNTs FFs • α π υ α

απ α απ αυ υ α π

• υ α α FFs

π α α:

Opioids for the management of BTcP: systemic Review Zeppetella G, Davis A. Cochrane Library 2013

• α υ π απ υ α FF (fast fentanyls)

• α πα : PID Placebo α 60΄

χ :

10 RCTs (INFS, FPNS, FBT, FSL, OTFC, FBSF, oral MSIR)

INFS = FPNS > placebo α π FF α 5Σ INFS > π FF α 10Σ INFS > FPNS = FBT = OTFC > π FF α 15Σ INFS > FPNS = FBT = OTFC = FST =FBSF > oral morphine and placebo α 30Σ Oral Morphine > placebo α 45Σ

• Ό α α FF > oral morphine > placebo • INFS α α π ( ) BTcP

υ π α α:

A network metaanalysis of the efficacy of opioid analgesics for the management of BTcP episodes

Zepetella G, Davies A., Eijgelshoven I, Jansen JP J. Pain Sympt.Manage 2014 47:772-785

Φ α α FF α α π υ α υ BTcP, υ

χ υ profil

χ :

Pubmed 64 α Ρ99 Ρ12 100 INFS

400 FBT

600 OTFC

:

Cmax 0,7 Ν 0,95 /ml

α πα (Darwish Ρ07, Kaasa Ρ10, Lennernes Ρ05)

υ α α :

BTcP: FF, α π BTcP A review of the pharmacokinetic profil of transmucosal fentanyl formulations N. Moore et al Curr Med. Rep Opin, 2012

• Φ πα αφ υ α α α, , α Ν φ

• 3 Φ π

π α α:

α α α C max 15Σ α α απ

α α α C max 30Σ α α αυ . υ / C max 60Σ

απ

π

π π

BTcP: FF, α π BTcP A review of the pharmacokinetic profil of transmucosal fentanyl formulations N. Moore et al Curr Med. Rep Opin, 2012

α υ α υ υ (slow):

α υ υ (fast):

σuneΣz Olarte EAPCRC, 2014 Lleida

BTcP: π FF, α π BTcP;

• αφ α • :

α α υ α α α α α

α α φα α α π υ α α

α α υ υ

α α υ υ α α α α π υ BTcP:

WHO 2012

Ρ90 α

AssPM of GBr. and Ireland

Davis et al 2009

ESMO 2012

BTcP

Γα α 2012 FSSTP

FSAPL

FASCP

NCCN

2013

2011

απω α 2012 JPCS

πα α 2013 SEOM

SSPC

SSP

EONS 2013

Eur. Ong. Nurs. Soc.

EAPC 2012

Caraceni, Hans, Kaasa

Delphy cons

EPCRC 2011

α υ υ α υ

• υπ π π π α α υ α π α α

• α π π α α υ π ( : φ 60mg, Fent TTs 25 , υ

30mg, φ 8mg, υ φ 25mg) (FDA Ρ11, REεS Ρ11)

• α ROO (IV φ α FF) π α π α απ α α υ BTcP

• π α BTcP π π απα α α α α π α υπ π

• α α α =1/6 24 , α SAO (Zeppetella Σ11, Σ13)

χυ υ (Grading system α Guyatt Ρ08)

BTcP: π α υ υ ω α υ ω

• υπ α α α FF 24 υ π α υπ π

( 1-72% 24 ) (Davis Ρ09)

• υπ α α α α FF • πα α π α FF α α

α (εercadante Σ09)

• π π α υ υ (FDA Ρ12)

• π π α α υ π α π Σ α

χυ υ (Grading system α Guyatt Ρ08)

• FF: REMS (Risk Evaluation and Mitigation Strategy)

BTcP: π α υ υ ω α υ ω ( υ χ α)

• α α FF (Zeppetella Ρ11) • υ απ FF α π

( ercadante Σ13, α Σ ) • υ απ υ FF α α

>120 mg M/24 α α π (εercadante Σ11)

• >5 π α BTcP/ = α απ α 24

• 20΄ π • α Ν 20Σ Ν 30Σ π

BTcP

• υ α Ν 20Σ -30Σ π π απ υ πα α

• α < 4 = monitoring • α :

- π - απ υ πα α - π - υ

• ESετ Σ12: SAτ: • E PC Σ12: Rττ:

• Γα α Σ12: Rττ:

• πα α Σ13: SAO:

ROO:

BTcP: φυ α χ SAO - ROO

• π υ BTcP - α

• α π υπ υ - α α (fast – slow BTcP)

• φα α υ - α φ α α • Θ Θ Γ

α Φ . α α

υ

BTcP: π π ;

• π φ α α 2009

• π φ α 2014

• α υ υ α υ πα 2013

α α Θ απ α υ α α Φ α ( Η. . . )

• α α α α 1

- απ α α α πα - υ (head to head) FF - π - α - υ / φ υ

• BTcP υπ π (survivors);

1. Davis A, Zeppetella G 2014

A review article that high lights reduced pain indencity / meaningful pain relief

as parameter across FF studies

BTcP: π π ω;

υχα

α υ α πα (BTcP):

π υ α α;