3LE COMPONENTI DEL DOLORE ONCOLOGICO Dolore di base o persistenteBreakThrough cancer Pain (BTcP)What is BTcP? It occurs in patients with cancer who have persistent pain. i.e. pain that is experienced for at least 12 hours per day and is managed with ATC medication. BTcP is a transitory exacerbation of pain experienced by the patient who has relatively stable and adequately controlled baseline pain. BTcP requires independent assessment and targeted treatment.The graphic illustrates how BTcP “breaks through” the level of analgesia provided by around-the-clock (ATC) medication used to control a patient’s persistent pain.ReferencesPortenoy et al. Oxford Textbook of Palliative Medicine (3rd ed) Oxford University Press, Oxford, 438–458.Bennett D, Burton AW, Fishman S, et al. Consensus panel recommendations for the assessment and management of breakthrough pain. Part II—management. Pharm Ther 2005;30:354–361.O1-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;30:3-Zeppetella G. et al. Curr Op Supp Pall CareRealizzato con il contributo non condizionato di Cephalon
4Characteristics of BP Frequency 30-90% Moderate to severe intensity Rapid onset (<3 minutes in 43% of patients)Often unpredictableRelatively short duration (30-60’)Frequency: 1-4 episodes per dayFeatures:Physical consequencesPsychological consequencesSocial consequencesResource consequences
8Prima definizione:“BTcP is a transitory increase in pain to greater than moderate intensitywhich 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).
9Supportive Care Cancer 2010 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, Rossella Restuccia, 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
11Pts admitted in APRPC were divided in the following classes, according to the level of background pain intensity and analgesic drugs used at admission (T0):Patients with no pain-mild pain NO opioidsPatients with mild pain receiving weak opioidsPatients with moderate pain receiving weak opioidsPatients with severe pain receiving weak opioidsPatients with mild pain receiving strong opioidsPatients with moderate pain receiving strong opioidsPatients with severe pain receiving strong opioidsPatients with severe pain, receiving NO opioidsPatients with moderate pain, receiving NO opioids.
12MEANINGFUL 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.
13Dolore 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).13
14Construct for opioid titration in incident pain Analgesic lineToxicity lineDoseDose for pain on movementDose for pain at restIncident pain can be an expression of poor basal pain control. It may be possible to prevent or limit the intensity of pain induced by movement by increasing opioid doses to the top of the therapeutic window.1Recent animal studies of metastatic bone pain suggest that similar pain intensities induced by different stimuli (i.e. cancer cells injected in bone or inflammatory stimulus) may have different sensitivities to opioids.1Reference:1. Mercadante S et al. J Pain Symptom Manage 2004; 28:EffectsMercadante S et al. Optimization of opioid therapy……J Pain Symptoms Manage 200414
15Balancing Analgesia and Side Effects The goal of opioid therapy is to achieve maximal analgesia with minimal side effects.This means that side effects should be managed aggressively and that opioids should be dosed in a manner that matches opioid blood levels with the intensity of pain. The goal is to achieve the optimal balance between analgesia and side effects.
16Ideal Breakthrough Pain Medication Rapid onsetShort duration of effectMinimal side effectsNoninvasive, easy-to-useCost-effectivePortenoy RK, Hagen NA. Pain. 1990;41:16
18Short-acting opioids are the mainstay of pharmacological treatment1 Due to its nature, breakthrough cancer pain requires a treatment that:Has a fast onset of action2Is appropriate in its potency3Is easily administered3The WHO analgesic ladder recommends background pain is controlled with around-the-clock analgesia4Issues with opioids:1Only effective if breakthrough cancer pain is an opioid-responsive pain1Only effective if onset of action reflects the duration of the episode1Breakthrough cancer pain is distinct from background pain.1Patients suffer an average of 2-4 episodes of breakthrough cancer pain per day.2,3Breakthrough cancer pain is:2Rapid in onset (<3 minutes in 43% of patients)Transitory (median 30 minutes)Evident in patients with otherwise stable and adequately controlled background painReferences:1. Zeppetella G and Ribeiro MDC. Opioids for the management of breakthrough (episodic) pain in cancer patients. The Cochrane Database of Systematic Reviews 2006.2. Portenoy RK and Hagen NA. Pain 1990; 41:3. Hojsted J et al. Acta Anaethesiol Scand 2006; 50:1. Davies AN. Brit J Hosp Med 2006; 67: Mercadante S et al. J Pain Symptom Manage 2004; 27: Mercadante S et al. Cancer 2002; 94: World Health Organisation. WHO analgesic ladder for cancer. Accessed 09/06/07.
19Dolore persistente trattato con terapia oppioide TRATTAMENTO DEL BTcPIl trattamento ideale dovrebbe coprire tutta la variabilità degli episodi di BTcP3’60’DurataDurataDurataDurataIntensitàA: Inter individual variably is important: A physician or a hospital with a big number of patients who want only to prescribe or to reference one or two BTcP medicines should choose one that covers a maximum of situations.Intra-individual variably is very important. A patient should have a medicine that covers if possible every BTcP.The Ideal treatment should cover all BTcP Episodes.F: What are the advantages of FBT in this case?Dolore persistente trattato con terapia oppioideTempo1919
20Flexible use of oral morphine Anticipated before starting activity(approximately 30’ before)Patients happy with… one shot…Slow onset BP20
21Main 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..?)
22BTcP Therapies: Delivery Systems MERCADANTE, DRUGS 2012 19982006/20082009200820092009Oral trans -mucosal fentanyl citrate OTFCFENTORA®(US)/ EFFENTORA™(EU)ONSOLIS™(US) FBSFRapinyl™/Abstral(EU) SLFInstanyl™(EU) INFSNasalFent ® (EU) FPNSSeveral delivery systems are available today and many more are under developmentThey use different route of administration none of them is oral because of the first pass effect and implementThey can be grouped into two broad categories based on the route of administration:Buccal/sublingual and nasalOralTransmucosalLozengeEffervescent BuccalTabletFentanyl BuccalSoluble FilmSublingualFentanylIntranasalFentanyl SprayyFentayl PectinNasal Spray222222
23BTcP Therapies: Early Absorption parameters ActiqEffentoraOnsolisAbstralInstanylNasalfentDose(mcg)40050-200Dwell Time(min)1515-20N/ACmax(ng/mL)0.60.90.72.51.5Tmax120(30–240)45(20–240)60-(23–240)(6-90)20(5-90)2323
24Pts should be assessed for the presence of BtcP – D Pts 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 - D2424
27Respiratory function during parenteral opioid titration for cancer painEstfan et al, Palliat Med 2007Before titration Pain controlPain scoreOpioid dose
28Significant relationship (p<0.001) Dose of breakthrough oral opioid versus ATC dose from the four studies of OTFCSignificant relationship (p<0.001)High variability12010080604020Hagen et al. J Palliat Med 200728
29The dose of the oral rescue dose was on average 18% of the ATC dose Zeppetella J. Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief. JPSM 200850 pts250 episodesThe dose of the oral rescue dose was on average 18% of the ATC doseFor OTFC, the rescue dose was approximately 36% of the ATC dose2929
30OTFC versus IV-morphine for breakthrough pain. Efficacy and safety of IV bolus of morphine for episodic (breakthrough) pain. Mercadante et al, JPSM, 2004Intravenuos morphine for breakthrough pain in an acute pallliative care unit: a confirmatory study.Mercadante et al JPSM 2008OTFC versus IV-morphine for breakthrough pain.Mercadante et al, Br J Cancer 2007
31293 episodi di BTcP trattati con P e T. DOSING FENTANYL BUCCAL TABLET FOR BREAKTHROUGH CANCER PAIN: DOSE TITRATION VERSUS PROPORTIONAL DOSES.Mercadante et al, CMRO 2012126 mg di equivalenti di morfina (range 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< ). 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
32Pain 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)
33No 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
34ConclusioneIl 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 osseeDovranno 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 trattamento3434
35Breakthrough 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 eventsStudies ongoing