1. Cancer pain management Using evidence to support practice Mike Bennett Professor of Palliative Medicine Lancaster University

2. Cancer pain epidemiology

3. Prevalence Systematic reviews Systematic reviews – 48% of patients with early stage cancer – 59% undergoing cancer treatment – 64-75% with advanced disease Hearn and Higginson 2003 Van den Beuken-van Everdingen et al 2007 Surveys (n=5000) Surveys (n=5000) – 72% of European community patients – 77% in UK Breivik et al 2009

4. Severity Secondary care settings Secondary care settings – Using 0-10 rating scale (0=no pain, 10=worst) Average pain = 3.7 Average pain = 3.7 Maximum pain = 4.8 Maximum pain = 4.8 – Two thirds of patients rate greater than 5/10 Klepstad et al 2002, Yates et al 2002 Community settings (n=617 in UK) Community settings (n=617 in UK) Average pain = 6.4 Average pain = 6.4 – 90% rated greater than 5/10 – 25% not receiving any analgesia

5. Longitudinal data – 116 cancer patients followed-up from 3 months to death – EORTC QLQ C30 monthly intervals – Pain bothered ‘quite a bit’ or ‘very much’ in 57-59% of patients only 5% experienced improved pain before death Elmqvist et al Supp Care Cancer 2009

6. Prescribing data Pain Management Index – analgesic prescription (0-3) MINUS level of pain (0-3) – negative score suggests under treatment Review of 26 studies – Prevalence of negative PMI in 8 - 82% populations studied – weighted mean = 43% – nearly 1 in 2 patients were ‘undertreated’ Deandrea et al Ann Onc 2008

7. Proportion of cancer patients in the weeks preceding death who were prescribed analgesics (N=234) Borgsteede et al 2008

8. Proportion of non-cancer patients in the weeks preceding death who were prescribed analgesics (N=188)

9. Costantini 2008, BMC Cancer

10. WHO ladder - is it effective?

11. History of the ladder 1980 – WHO establishes Cancer Control Programme – Cancer prevention – Early diagnosis with curative treatment – Pain relief and palliative care 1986 – ‘Method for relief of cancer pain’ 1996 – revised edition published

12. History of the ladder Best regarded as a framework of principles and not a rigid protocol Advocates analgesia: – By the mouth, by the clock, by the ladder – Individualised to patients – Attention to detail Put oral opioids on the map

13. WHO ladder in practice

14. Common mis-interpretations: – starting at step 1 for moderate to severe pain – assuming that the ladder is restricted to opioids – rotating around analgesics at steps 1 or 2 despite inadequate pain relief

15. WHO ladder in practice Analgesics are the cornerstone of good cancer pain management – in contrast to management of non-cancer chronic pain But reducing barriers to pain management also important – educating patients and carers – access to medicines – ………more on these aspects another time!

16. Effectiveness of the ladder as a whole....but first some questions about your practice

17. Do you: – use step 2 before step 3? and do you think step 1 added to step 3 makes a difference? – initiate strong opioids using immediate release opioids before converting to sustained release? – use morphine as first line strong opioid or do you believe that other opioids are better? – believe that a high proportion of patients need to be ‘switched’?

18. Effectiveness of the ladder as a whole Early evidence Many observational studies 1985-90 – Reported proportion of patients that achieved adequate control – 3220 patients studied 2361 (73%) achieved control – One study documented pain scores 1229 patients; mean reduction in pain intensity >65% Ventafridda et al 1987 – Around 25% of patients do not get adequate pain control

19. Effectiveness of the ladder as a whole Later studies Prospective 10 year study – 2118 patients with cancer pain – data at days 0, 6, 37, 66 (mean intervals) – opioids given orally (83%) parenterally (9%) spinally (2%) – range of co-analgesics too Zech et al 1995 Pain

20. Effectiveness of the ladder as a whole Later studies Pain relief – Good 76% – Satisfactory 12% – Inadequate 12% No differences in pain intensity or relief between types – but those with NeuP received significantly more co-analgesics Zech et al 1995 Pain Grond et al 1999 Pain

21. Effectiveness of the ladder as a whole Systematic reviews 1995 – 8 studies (1982-1995) – Meta-analysis not possible – ‘adequate pain management in 69-100%’ Jadad and Browman 1995 JAMA 2006 – 17 studies (8 overlap with earlier review) – ‘adequate pain management in 45-100%’ Ferriera et al 2006 Supp Care Cancer

22. Evidence base for specific aspects

23. Evidence base for specific aspects EAPC guidance European Association for Palliative Care – Guidance on using strong opioids 1996 updated 2001 – 20 recommendations

24. Evidence base for specific aspects EAPC guidance WHO ladder EAPC guidance By the mouth oral route preferred By the clock start with normal release before modified release By the ladder morphine preferred strong opioid methadone not recommended for non-specialists Individualised for patients switch opioids if side effects occur

25. Evidence base for specific aspects EAPC guidance WHO ladder EAPC guidance By the mouth oral route preferred By the clock start with normal release before modified release By the ladder morphine preferred strong opioid methadone not recommended for non-specialists Individualised for patients switch opioids if side effects occur

26. Evidence base for specific aspects ‘ By the mouth’ Cochrane review of oral morphine – Clinical trial evidence small Wiffen 2007 Oral versus transdermal studies – randomised, but non-blind – similar analgesia but less adverse effects with transdermal route ?drug or delivery system van Serventer et al 2003 Curr Med Res Opin

27. Evidence base for specific aspects EAPC guidance WHO ladder EAPC guidance By the mouth oral route preferred By the clock start with normal release before modified release By the ladder morphine preferred strong opioid methadone not recommended for non-specialists Individualised for patients switch opioids if side effects occur

28. Evidence base for specific aspects ‘By the clock’ Normal release opioids first? – Randomised, parallel study NR vs SR opioids in 40 patients previously on weak opioids Both groups achieved adequate pain relief – 2.1. days NR vs 1.7 days SR – SR group reported less tiredness Klepstad et al 2003 Pain – Cochrane review Supports titration using modified release preparations Wiffen and McQuay 2007, Cochrane Database

29. Evidence base for specific aspects ‘By the clock’ Regular dosing? – Randomised, crossover studies of ‘as needed’ opioid injections vs subcutaneous infusion – 2 studies (n=22, n=12) over 6 days 48 hours on each system then crossed over – Total opioid doses similar – Pain scores similar and preferences equal Bruera et al 1988 J Natl Cancer Inst Watanabe et al 2008

30. Evidence base for specific aspects ‘ Single or double dose at night?’ EAPC guidelines suggest double dose of oral immediate release morphine at night Study 1 – Open, randomised cross-over, n=20 (Davies et al 2002) – DD group; higher pain scores, more breakthrough doses, worse opioid side-effects (vivid dreams, dry mouth) Study 2 – Blinded randomised cross-over, n=19 (Dale et al 2009) – clinical equivalence between groups

31. Evidence base for specific aspects EAPC guidance WHO ladder EAPC guidance By the mouth oral route preferred By the clock start with normal release before modified release By the ladder morphine preferred strong opioid methadone not recommended for non-specialists Individualised for patients switch opioids if side effects occur

32. Evidence base for specific aspects ‘By the ladder’ 2-step or 3-step ladder best?

33. Evidence base for specific aspects ‘By the ladder’ Evidence for advantage in moving from step 1 to step 2? 2 large reviews of NSAIDs +/- weak opioid Lack of evidence to support significant improvement in pain between these steps Eisenberg et al 1994 JCO McNicol et al 2004 JCO Additional reduction in pain when adding paracetamol to strong opioid – 0.4 – 0.6 on 0-10 rating scale Stockler et al 2004, JCO

34. Evidence base for specific aspects ‘By the ladder’ Step 1 to step 3 safe? – 2 randomised non-blind trials in opioid naïve patients – allocated to strong opioids straight away or step-wise (WHO ladder) approach – strong opioid ‘straight away’ group better pain relief more nausea, anorexia and constipation – Design problems open baseline pain scores differed in one trial (WHO group worse) Marinangeli et al 2004 J Pain Symptom Manage Maltoni et al 2005 Supp Care Cancer

35. Evidence base for specific aspects EAPC guidance WHO ladder EAPC guidance By the mouth oral route preferred By the clock start with normal release before modified release By the ladder morphine preferred strong opioid methadone not recommended for non-specialists Individualised for patientsswitch opioids if side effects occur

36. Morphine or oxycodone first? RCT cross-over design – 32 patients received Mor or Oxy, then switch after 1 week – 23 completed Pain scores, side effects and preferences similar Bruera et al 1998, JCO

37. …..another RCT in 45 patients – 27 completed – Pain control similar More vomiting with morphine (but nausea same) More constipation with oxycodone No other differences in adverse effects Heiskanen and Kalso 1997, Pain

38. Meta-analyses Oxycodone in head to head trials – No differences in pain or adverse effects overall against morphine or hydromorphone Reid et al 2006, Ann Oncol

39. Morphine or fentanyl first?

41. Methadone – Very cheap, more available in developing countries – Double blind RCT methadone vs morphine, n=103 Both groups 20% reduction in pain More dropouts in methadone group Methadone not superior to morphine Bruera et al 2004 JCO

42. Evidence base for specific aspects EAPC guidance WHO ladder EAPC guidance By the mouth oral route preferred By the clock start with normal release before modified release By the ladder morphine preferred strong opioid methadone not recommended for non-specialists Individualised for patients switch opioids if side effects occur

43. Evidence base for specific aspects ‘Individualised to patients’ Prospective observational study – 186 patients commenced on morphine – 47 (25%) did not respond and needed to switch 37/47 did well on oxycodone 10 needed additional switches Riley et al 2006, Supp Care Cancer

44. Evidence base for specific aspects ‘Individualised to patients’ Systematic review of ‘switching’ – 31 observational studies, small numbers 12% required a switch Most patients appeared to benefit – 60-70% patients experienced benefit – median morphine dose fell from 577 to 336mg Mercadante and Bruera 2006 Cancer Treat Rev

45. WHO analgesic ladder: is it effective in cancer pain? WHO ladder directly observed in 5000 patients – 75% achieve good control compare that with amitriptyline or gabapentin in neuropathic pain – current evidence supports flexibility when using WHO ladder – some recommendations may need revising the broad approach does not

46. WHO analgesic ladder: is it effective in cancer pain? Framework of principles – most important contribution as an educational tool – probably qualifies as MRC ‘complex intervention’ challenging to define and measure effectiveness Poor implementation accounts for under- treatment of cancer pain

47. Thank you m.i.bennett@lancaster.ac.uk