1. Appropriattezza ed inappropriatezza della prescrizione di Analgesici Federica Aielli Dipartimento di Scienze Cliniche Appllicate e Biotecnologiche Università degli Studi dell’Aquila

2. Treatment of cancer pain WHO’s Pain Relief Ladder

3. ESMO Clinical Practice Guidelines 2012

4. WHO Step II opioids  Mild-moderate pain: Weak opioids: CodeineTramadol Rodriguez RF, et al. J Palliat Med 2007:  no difference in efficacy between tramadol, codeine plus paracetamol, and hydrocodone plus paracetamol  tramadol was associated with more side-effects Tassinari D, et al. Palliat Med 2011:  Codeina and tramadol are effecive compared with placebo

5. Is codeine some morphine?  0-15% of codeine is demethylated to morphine by CYP2D6 (high genetic polymorphism)  7-10% are poor metabolizers….  Poor metabolizers had no analgesia with codeine (Sintrup, 1993, Poulsen, 1996)

6. Wilder-Smith CH, et al. Oral tramadol, a μ-opioid agonist and monoamine reuptake-blocker, and morphine for strong cancer-related pain. Ann Oncol 1994  The mean pain intensity was similar with morphine and with tramadol  The total number of side-effects per person was lower on the fourth day with tramadol (p < 0.05),  the severity of nausea (p < 0.05) and constipation decreased with tramadol (p < 0.05).  Three patients dropped out of the morphine group due to side-effects and 4 out of the tramadol group due to inadequate analgesia.

7. Wilder-Smith CH, et al. Oral tramadol, a μ-opioid agonist and monoamine reuptake-blocker, and morphine for strong cancer-related pain. Ann Oncol 1994  Rated pain control better with morphine (p < 0.03), but the tolerability of tramadol was judged superior (p < 0.002).

8. The use of strong opioids, particularly with TTS fentanyl, in opioid naive patients to by-pass the second step drugs. Critical point: opioid starting doses Mistakidou 2002, 0.6 mg fentanyl, Marinangeli, 2004, unknown, presumably morphine equivalent 60 mg Maltoni 2005, morphine equivalent 60 mg According to this information it should be assumed that doses of 0.6 mg/day of TTS fentanyl or equivalent doses of 60 mg/day of oral morphine, can be safety used in opioid-naive pts. Vilkmayer 1999, 0.6 mg fentanyl, more AE van Seventer et al,2003, only about half patients completed the 4 week period Tawfik et al,2004, opioid-naive patients receiving 0.6 mg/die of TTS fentanyl developed relevant AE in comparison with tolerant pts and were more likely to withdrew because of AE What is the tolerated starting dose in opioid naive pts having moderate pain? Doses of about 60 mg/day in naive-patients are likely to produce drop-out due to AE

9. Opioids: low doses in opioid-naive patients  Mercadante S, Porzio G, Ferrera P et al “Low morphine doses in opioid-naive cancer patients with pain.” J Pain Symptom Manage 2006 Mar;31(3):242-7.  Mercadante S, Porzio G, Ferrera P et al “Low doses of transdermal buprenorphine in opioid-naive patients with cancer pain: a 4-week, nonrandomized, open-label, uncontrolled observational study.” Clin Ther 2009 Oct; 31(10):2134-8

10. Opioids: low doses in opioid-naive patients  Mercadante S, Porzio G, Ferrera P et al “Low doses of transdermal fentanyl in opioid naive patients with cancer pain” Curr Med Res Opin. 2010 Dec;26(12):2765-8  Mercadante S, Porzio G, Ferrera P, Aielli F, Adile C, Ficorella C, Giarratano A, Casuccio A. Tapentadol in cancer pain management: a prospective open-label study. Curr Med Res Opin. 2012 Nov;28(11):1775-9

11. Opioids: low doses in opioid- naive patients N° pazienti Dose T0Dose T4 Basse dosi morfina10215 mg45 mg Basse dosi buprenorfina 310,3 mg0,67 mg Basse dosi Fentanyl390,4 mg0,8 mg Basse dosi Tapentadolo50100 mg200 mg

12. Opioids: low doses in opioid- naive patients Pain Intensity T0Pain Intensity T4giorni Basse dosi morfina6,132 Basse dosi buprenorfina 6,431,5 Basse dosi Fentanyl6,43,21,7 Basse dosi Tapentadolo621,7

13. Opioids: low doses in opioid- naive patients T0T1T4 Nausea/vomito0,1-0,80,2-0,90,1-0,8 Stipsi0,4-0,50,4-0,91,2-1,8 Sonnolenza0,1-0,30,6-0,80,5-0,7 Confusione0,1-0,40,2-0,50,2-0,4 Scala da 0 a 3

14. A question of dosing… The use of low doses of strong opioids in naive patients.

15. Management of cancer pain: ESMO Clinical Recommendations 2012  Weak opioids such as codeine, tramadol and dihydrocodeine should be given in combination with non-opioid analgesicsAs [III, C]  An alternative to weak opioids, consider low doses of strong opiods in combination with non-opioid analgesics. [III, C]

16. The role of the second step of the WHO analgesic ladder is still open!

17. WHO Step III opioid first choice  Morphine is the prototype opioid analgesic, and for 25 years oral morphine has been deemed the drug of first choice for treating moderate to severe cancer pain.  Novel formulations of old opioids, such as oxycodone, hydromorphone, Buprenorphine and fentanyl and new opioids such as tapendadol have been developed and the availability of different opioids across the world has improved.

18. WHO Step III opioid first choice  Morphine has remained the first choice for reasons of familiarity, availability, and cost rather than proven superiority.  The data show no important differences between morphine, oxycodone, and hydromorphone given by the oral route and permit a weak recommendation that any one of these three drugs can be used as the first choice step III opioid for moderate to severe cancer pain

19.  All the three opioids used as first-line therapy:  were effective,  well tolerated,  required similar amounts of symptomatic drugs or co- analgesics.  Methadone was significantly less expensive, but required more changes, of the doses, suggesting that dose titration of this drug requires major clinical expertise. “Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management.” Mercadante S, Porzio G, Ferrera P, et al. Eur J Pain. 2008

20.  No statistical differences in changes in pain and symptom intensity.  No significant changes in rescue doses of oral morphine were reported at the same intervals.  Cancer patients receiving stable doses of TTS FE or TTS BU can be safely switched to the alternative transdermal opioid “Switching from Transdermal Drugs: An Observational ‘‘N of 1’’ Study of Fentanyl and Buprenorphine” Mercadante S, Porzio G, et al. J Pain Symptom Manage 2007

23. Role of paracetamol and NSAIDs

24. The role of paracetamol and nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the control of pain in advanced cancer. A systematic review of the literature. Nabal M, et al. Pall Med 2012  The evidence from the available clinical trials is of limited amount and quality, but it weakly supports the proposal that the addition of an NSAIDs to WHO Step III opioids can improve analgesia or reduce opioid dose requirement.  There is insufficient evidence to support the use of paracetamol in combination with Step III opioids.  Data on the toxicity of NSAIDs in this indication are insufficient owing to the small number of patients and the short duration of treatment reported in the studies.

25. Nonopioid drugs in the treatment of cancer pain. Vardy J, Agar M, J Clin Oncol 2014  Most of the acetaminophen and NSAID studies in patients with cancer had small sample sizes and were of short duration, and none included selective COX-2 inhibitors.  Longer term efficacy and safety remain unknown, with prevalence and severity of toxicities not quantified in patients with cancer.  Studies have not been adequately powered to determine whether NSAIDs or acetaminophen are more beneficial for certain types of cancer pain, although anecdotally, it is suggested that NSAIDs are more effective for pain associated with inflammation

26. Role of paracetamol and NSAIDs in addition to opioids  ESMO Clinical Practice guideline: no information no information  EAPC evidence-based recommendations: weak recommendation to add NSAIDs to step III opioids to improve analgesia or reduce the opioid dose required to achieve analgesia.

27. Neuropathic pain:  Tricyclic antidepressants (amitriptyline, imipramine)  Antiepilectics (gabapentin, pregabalin) ESMO Clinical Practice guideline:  Patients with NP should be treated with non opioid and opioid drugs [III, B].  Patients with NP should be given either a tricyclic antidepressant or a anticonvulsant and subjected to side effects monitoring [I, A].

28. EAPC evidence-based recommendations: strong recommendation that amitriptyline or gabapentin should be considered for patients with neuropathic cancer pain that is only partially responsive to opioid analgesia

29. Mercadante S, et al. The effects of low doses of pregabalin on morphine analgesia in advanced cancer patients. Clin J Pain. 2013 Jan;29(1):15-9  48 patients completed the study, 30 and 18 patients in groups MO and MO-PR, respectively  No statistical differences were observed.  No differences were found in quality of life and all BPI items  10 patients had a definite neuropathic pain; as expected, this did not indicate a significant difference

30. Bennett MI, et al. Pregabalin for the management of neuropathic pain in adults with cancer: a systematic review of the literature. Pain Med. 2013 Nov;14(11):1681-8  The studies included one double-blind randomized controlled trial, one single-arm open-label study, two observational analyses, and one case report  Not possible to draw any conclusions on the descriptive summary of pregabalin for the treatment of cancer related neuropathic pain

31. Adjuvant drugs?  only selected patients (highly responsive)  the drugs should not be initiated at once  ” add on” strategy

32. WHO’s Pain Relief Ladder FANS Oppioidi deboli ± adiuvanti Oppioidi forti ± adiuvanti Oppioidi forti Oppioidi forti + adiuvanti Rotazione Tecniche Invasive WHO’s Pain Relief Ladder: 2016