Sebastiano Mercadante, MD

Professor of Palliative Medicine, University of PalermoDirector Anesthesia & ICU - Pain Relief & Palliative Care Unit

La Maddalena Cancer Center, Palermo – Italy

https://www.bmedonline.it/s-cfpaff/4631.html

Realizzato con il contributo non

condizionato di Cephalon

1-Portenoy RK, et al. Oxford Textbook of Palliative Medicine (3rd ed). Oxford: Oxford University Press; 2004:438-582-Bennett D, et al. Pharmacy & Therapeutics. 2005;30:354-61.3-Zeppetella G. et al. Curr Op Supp Pall Care

Dolore di base o persistenteDolore di base o persistenteDolore di base o persistenteDolore di base o persistente BreakThrough cancer Pain BreakThrough cancer Pain (BTcP)(BTcP)BreakThrough cancer Pain BreakThrough cancer Pain (BTcP)(BTcP)

LE COMPONENTI DEL DOLORE ONCOLOGICO

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) PainConsensus 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 theEuropean Association for PalliativeCare (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).

?

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).

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Breakthrough pain in oncology: a longitudinal studySebastiano Mercadante MD *°, Enrico Breda, MD +, Carlo Arcara, MD #, Vittorio Gebbia, MD #, Giampiero Porzio, MD #, Federica Aielli, MD #, Fabrizio David, MD*, Teresa Gammucci, MD^, Filomena Narducci, MD^ , Gaetano Lanzetta, MD @, Rossella Restucci a, MD @, Alessandro Lembo, MD ¶, Virginia Passeri, MD ¶, Vladimir Virzì, MD » Alessandra Casuccio BS $,

♦ 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 opioidsb.Patients with mild pain receiving weak opioids c.Patients with moderate pain receiving weak opioids d.Patients with severe pain receiving weak opioidse.Patients with mild pain receiving strong opioids f.Patients with moderate pain receiving strong opioidsg.Patients with severe pain receiving strong opioidsh.Patients with severe pain, receiving NO opioidsi.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: prognosiDolore 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 Construct for opioid titration in incident pain incident pain

Analgesic line

Toxicity line

Dose for pain at rest

Dose for pain on movement

Effects

Dose

Mercadante S et al. Optimization of opioid therapy……J Pain Symptoms Manage 2004

Balancing Analgesia and Side Effects

Ideal Breakthrough Pain Medication

• Rapid onset

• Short duration of effect

• Minimal side effects

• Noninvasive, easy-to-use

• Cost-effective

Portenoy RK, Hagen NA. Pain. 1990;41:273-281.

Oral Morphine Profile

BTP Profile Overmedication

Pain relief gap

Time (minutes)5 30 60

Pa

in In

tens

ityBTP Profile

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.

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• Il trattamento ideale dovrebbe coprire tutta la variabilità degli episodi di BTcP

TRATTAMENTO DEL BTcP

Inte

nsi

tà

Tempo

Durata Durata Durata Durata

Dolore persistente trattato con terapia oppioide

3’ 60’

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 20121998 2006/2008 2009 2008

Oral trans-mucosal fentanyl citrateOTFC

FENTORA®(US)/ EFFENTORA™(EU)

ONSOLIS™(US) FBSF

Rapinyl™/Abstral

(EU) SLF

2009

Instanyl™(EU) INFS

2009

NasalFent ® (EU) FPNS

Effervescent BuccalTablet

Fentanyl Buccal Soluble Film

OralTransmucosal

Lozenge

Intranasal Fentanyl Sprayy

SublingualFentanyl

Fentayl Pectin Nasal Spray

BTcP Therapies: Early Absorption parameters

Actiq Effentora

Onsolis Abstral Instanyl

Nasalfent

Dose(mcg)

400100-1600

400100-800

400100-1200

400100-800

40050-200

400100-800

Dwell Time(min)

15 15-20 N/A N/A

Cmax(ng/mL)

0.6 0.9 0.7 0.7 2.5 1.5

Tmax(min)

120(30–240)

45(20–240)

60-

-(23–240)

15(6-90)

20(5-90)

Pts should be assessed for the presence of BtcP – DPts with BtcP should have this pain specifically assessed – DThe management of BtcP should be individualized – DConsideration should be given to treatmetn of the underlying cause of pain – DConsideration should be given to avoidance of the precipitating factors – DConsideration shoulc be given to modification of the background analgesia - DOpioids are the rescue medication pf choice – DThe dose should be determined by individual titration – BNon pharmacological methods may be useful – DNon-opioid analgesics may be useful – DInterventional techniques may be useful – DPts should have BtcP re-assessed - D

Respiratory function during parenteral opioid titration for cancer pain

Estfan et al, Palliat Med 2007

Before titration Pain controlPain score 6.8 1.9Opioid dose 73 169

0 100 200 300 400 500 600 700 800

120

100

100

80

60

40

20

0

Hagen et al. J Palliat Med 2007

Dose of breakthrough oral opioid versus ATC dose from the four studies of OTFC

Significant relationship (p<0.001)High variability

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

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)

Percentage of pts with adverse effects with an intensity of 1-2 on a 0-3 scale. No patient had intensity of 3

No differences in adverse effect intensity

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.

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