1. Cancer pain: Neuropathic pain and BTcP Sebastiano Mercadante, MD Director Anesthesia and Intensive Care Unit Pain Relief and Palliative Care Unit La Maddalena Cancer Center Palermo – Italy Professor of palliative medicine University of Palermo

2. Cancer pain is a mixed mechanism pain, rarely presenting as a pure neuropathic, visceral or somatic pain syndrome. Rather, it may involve inflammatory, neuropathic, ischemic, and compressive mechanisms at multiple sites Cancer pain is complex

5. Neuropathic Pain Syndromes in Cancer Patients Tumor related Brachial plexopathy Lumbosacral plexopathy Epidural spinal cord compression Compressive neuropathies Sciatic neuropathy, others

6. Non malignant Post-Mastectomy Pain Occurs in 5-20% of women More common with axillary dissection Can be quite severe and disabling Incidence probably declining Treatment Physical therapy Pain medications

7. Neuropathy induced by CH Vinka-alkaloids (vincristine) Taxanes (paclitaxel, docetaxel) Platinum (cis, carbo, oxali-platinum) Thalidomide Co-treatment, high cumulative doses Prevalence:10-100% Onset & severity depend on concomitant conditions: diabetes, alcholism, paraneoplastic

8. Paraneoplastic neuropathy Autoimmune response to an antigen on a nerve cell: - SCLC (1-30%) - Ovarian - Breast Dysesthesia, pain, initially distal, asymmetric Sensory neuropathy May preceed Anti-Hu (blood, nerve) Inflammation, gliosis

9. Assessment - Common scales, non specific to NP, sensitive to change ♠ McGill Pain Questionnaire ♠ Brief Pain Inventory - Specific scales, sensitive to changes ♠ Leeds Assessment of NP ♠ NP symptom inventory ♠ NP scale

14. Neuropathic pain It is considered a negative prognostic factor, but not absolutely Non responsive (Arner,1988) Poor prognostic factor (Bruera,1989) Opioid resistant (Portenoy,1989, Mercadante,1992, Jadad,1992) More likely associated to cognitive failure, probably because associated with higher doses (Mercadante,1997). Higher doses of opioids (Mercadante, 2009) Friends against pain & suffering

15. Non-opioids NSAIDs adjuvants Weak opioids Non-opioids NSAIDs adjuvants Strong opioids Non-opioids NSAIDs adjuvants Uncontrolled pain Persisting pain WHO analgesic ladder: still alive?

16. Amitriptyline in neuropatic cancer pain in patients on morphine therapy: a R-C study Mercadante et al, Tumori 2002 Analgesic effects No significant differences in pain intensity were found in a cross-over study, unless for “worst pain ” Adverse effects Drowsiness, confusion and dry mouth, significantly increased

17. Farmaci adiuvanti antiepilettici Caraceni et al, 2000 Gabapentin dose titration in 3-7 days up to 800-1200mg, 22 pts Decrease in global pain, burning pain, and shooting pain, as weel as allodynia... No changes in adverse effects, decrease in myoclonus...

18. Gabapentin is effective in the treatmnt of cancer- related neuropathic pain: a prospective, open-label study. Ross et al, J Palliat Med 2005 62 pts 300 to 1800 mg/day 25 Treatment - related 37 Tumor – related Attrition rate at day 15: n = 21 Mean dose: 1200 mg/day No differences in etiology (treatment v cancer) Tumor-related group 97 mg/day of morphine orally (no changes) Females more responsive?

19. Effectiveness of antiepileptic or antidepressant drugs When added to opioids for cancer pain: systematic review. Bennett M, Palliat Med 2010 465 pts 5 RCT studies (2 gabapentin, 1 amitryptiline, phenytoin, imipramine) 3 observational studies (2 gabapentin, 1 valproate) Gabapentin 1004-1395 mg Amitryptiline 50 mg Opioids kept stable or varied

20. Main conclusions  Opioids alone can be effective in NP  Best evidence for gabapentin  Reduction on >1 point, but more AE  Benefit within 1 week  Effect size less than that in non cancer NP (NNT and NNH different)  Combination of lower dose opioid and adjuvants resulted in better outcome Questions Adjuvants may improve pain outomes but requires skilful prescribing Low doses combinations of adjuvants? How was NP defined ?

21. Pregabalin Similar to gabapentin More potent Titration more feasible May low doses of pregabalin produce analgesia, independently from a neuropathic pain mechanism, reducing opioid escalation? Morphine and pregabalin Morphine alone 4 weeks

22. CRITERIA FOR SELECTING ANALGESICS FOR CANCER PAIN: DRIVERS IN DECISION Overall Efficacy Overall AE profile Individual clinical situation Pretreatment Pain intensity Pain mechanism Onset Comorbidity Interactions Abuse potential Cost Cultural influence Guidelines

23. Breakthrough pain “..the term is typically Am-English and does not have any correspondent in other languages in Europe..”. “..a broader and less burdened term could be episodic or transient pain” Mercadante & Expert Working Group of the EAPC Cancer 2002 “The term breakthrough pain is expanding now and more easily recognizable”

24. Optimisation of the opioid regimen Mercadante S et al. Cancer 2002 Mercadante S, et al. J Pain Symptom Manage 2004. Is breakthrough pain a function of inadequate pharmacological therapy? 1 –'end-of-dose failure' Does breakthrough pain occur only if baseline pain is well-controlled? –Patients suffering with frequent daily episodes often require re- assessment of the background opioid regimen 2 Mostly same location as baseline pain Higher basal pain intensity: more episodes Resistant pain related to the onset: spontaneous recovery

25. pain peaks Well controlled pain pain peaks Uncontrolled pain a: typical BP pattern, requiring rescue doses. b: uncontrolled basal pain requiring both optimization of basal analgesia and rescue doses during titration. c: changes in pain intensity of both basal analgesia and BP, obtainable after optimization of therapy a b c

26. 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.

27. Oral Morphine Profile BTP Profile Overmedication Pain relief gap Time (minutes) 5 30 60 Pain Intensity BTP Profile

28. Treating Cancer Pain–Ideal Ideal Breakthrough Medication Around-the-Clock Medication Persistent Pain Time Over Medication

29. Mu-opioid receptor agonist 1 – Brain, spinal cord, smooth muscle – Analgesia, sedation, respiratory depression, euphoria Estimated potency of 80 to 100 times that of morphine 2 1. Anderson R et al. J Pain Symptom Manage. 2001;21:397-400. 2. Pereira J et al. J Pain Symptom Manage. 2001;22:672-687. Fentanyl

30. BTcP Therapies: Target Product Profile Concentration–time profile that closely mirror the pain intensity–time profile of the BTcP episode Delivery systems with potential to: –Enhance dissolution –Enhance absorption –Minimize the first-pass effect

31. BTcP Therapies: Delivery Systems 199 8 2006/2 008 200 9 200 8 Oral trans -mucosal fentanyl citrate OTFC FENTORA ® (US)/ EFFENTORA™(EU) ONSOLIS ™ (US) FBSF Rapinyl ™ / Abstral (EU) SLF 200 9 Instanyl ™ (EU) INFS 200 9 Nasalfent ® (EU) FPNS Effervescent Buccal Tablet Fentanyl Buccal Soluble Film Oral Transmucosal Lozenge Intranasal Fentanyl Spray Sublingual Fentanyl Fentayl Pectin Nasal Spray

32. Buccal/Sublingual –Actiq – Effentora™ –Onsolis™ –Rapinyl™/Abstral Intranasal –Instanyl™ –NasalFent ® BTcP Therapies: Delivery Systems Cont.

33. BTcP Therapies: Early Absorption parameters ActiqEffento ra Onsoli s Abstra l Instan yl Nasalfe nt Dose (mcg) 400 100- 1600 400 100- 800 400 100- 1200 400 100- 800 400 50- 200 400 100-800 Dwell Time (min) 1515-20N/A Cmax (ng/mL) 0.60.90.7 2.51.5 Tmax (min) 120 (30– 240) 45 (20– 240) 60 - (23– 240) 15 (6-90) 20 (5-90)

34. Oral morphine oxycodone hydromorphone OTFC Effervescent fentanyl Oral methadone IV fentanyl Intranasal fentanyl T0 T15 T30 T45 Intravenous morphine Sublingual fentanyl The rush…... to meaningful pain relief A question of minutes… Mean duration of a BP event peak

35. 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

37. Portenoy RK, et al. Pain. 1999;79:303-312. Christie JM, et al. J Clin Oncol. 1998;16:3238-3245. Farrar JT, et al. J Natl Cancer Inst. 1998;90:611-616. Coluzzi PH, et al. Pain. 2001;91:123-130.

38. Main concerns about OTFC studies in breakthrough pain  BP type ? Incident ? Activity test?  66% of the episodes with placebo did not require additional dose medication (short-lived episodes? Placebo response?)  In less 42% of episodes OTFC produced a >33% change of PI‏ (morphine 31.8%...). Is it an effective dose?  Basal pain controlled (4 episodes/day)?  BP not severe enough: Mean basal PI 4.7 (with extremes 1-9)  Mean breakthrough PI: 6.8 (with extremes 2-10)  Many patients failed titration and dropped out without being considered  Pts on high doses do not find a successful dose...

39. 0 100 200 300 400 500 600 700 800 120 100 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

40. INTRAVENOUS MORPHINE FOR BREAKTHROUGH PAIN IN AN ACUTE PALLIATIVE CARE UNIT: A CONFIRMATORY STUDY. Mercadante, et al JPSM 2008 Even given in older pts or relatively large doses, IV-MO did not result in life-threatening AE in a large number of episodes (945 events) while being effective by patients in most cases. The mean dose of IV-M was 12 mg (95% CI 9-14 mg). In 8 episodes no changes in pain intensity were observed and a further dose of IV-M was given. The remaining pts did not require further interventions. No clinical events requiring medical intervention were recorded. The role of nurses is of paramount importance in monitoring and collecting data to gather information for audit purposes in the unit.

41. N° patients 25 Age 59 (55-63)‏ Gender (M/F) 12/13 Basal morphine dose 120 mg (96-144)‏ Doses (OTFC / IV-MO) events / patients 200 / 4 9 / 6 400 / 8 5 / 3 600 / 12 14 / 5 800 / 16 6 / 1 1200 / 24 13 / 8 1600 / 32 6 / 2 OTFC VERSUS IV-MORPHINE FOR BREAKTHROUGH PAIN S. Mercadante et al, Br J Cancer 2007

43. 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

44. Opioid titration 100 200 400 800 Proportional doses FBT for BTcP: dose titration versus doses proportional to opioids given for background analgesia Outcomes: - number of successful episodes - tolerability

45. Conclusion - Titration may be reduce patients' complicance - Titration has not been “scientifically” demonstrated to be superior - Doses proportional to the opioid basal regimen has been proven to be effective and safe with different ROO, facilitating prescription for BtcP in ambulatory and home care patients

46. Conclusion BP should be separately evaluated Characteristics stressed Optimization of opioid therapy Double prescription: specific as needed Choice according to timing and patient’s preference Selected cases require more expertise More data needed on new technologies

49. Normal pain transmission Periphery There is transduction of alterations in the milieu via specialized receptors Transduction occurs via primary afferents (Aβ, Aδ,c) Transmission in the primary afferents occurs via depolarization, with sodium and calcium channels playing a crucial role, to synapse in the dorsal horn Spinal cord Modulation of primary afferent input occurs. Excitation is via stimulation of postsynaptic receptors such as NMDA, substance P and descending serotonin release Inhibition is via GABA interneurones, opioid receptors, and desscending pathways (noradrenergic and serotoninergic) Glia cells are crucial to the regulation of neuronal activation