cancer pain management using evidence to support practice mike bennett professor of palliative...

Cancer pain management

Using evidence to support practice Mike Bennett

Professor of Palliative MedicineLancaster University

Cancer pain epidemiologyCancer pain epidemiology

PrevalencePrevalence• Systematic reviewsSystematic reviews– 48% of patients with early stage cancer48% of patients with early stage cancer– 59% undergoing cancer treatment59% undergoing cancer treatment– 64-75% with advanced disease64-75% with advanced disease

Hearn and Higginson 2003Hearn and Higginson 2003Van den Beuken-van Everdingen et al 2007Van den Beuken-van Everdingen et al 2007

• Surveys (n=5000)Surveys (n=5000)– 72% of European community patients72% of European community patients– 77% in UK77% in UK

Breivik et al 2009Breivik et al 2009

SeveritySeverity

• Secondary care settingsSecondary care settings– Using 0-10 rating scale (0=no pain, 10=worst)Using 0-10 rating scale (0=no pain, 10=worst)• Average pain = 3.7Average pain = 3.7• Maximum pain = 4.8Maximum pain = 4.8

– Two thirds of patients rate greater than 5/10Two thirds of patients rate greater than 5/10Klepstad et al 2002, Yates et al 2002Klepstad et al 2002, Yates et al 2002

• Community settings Community settings (n=617 in UK)(n=617 in UK)

• Average pain = 6.4Average pain = 6.4– 90% rated greater than 5/1090% rated greater than 5/10– 25% not receiving any analgesia25% not receiving any analgesia

• 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

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

Proportion of cancer patients in the weeks preceding death who were prescribed analgesics (N=234)

Borgsteede et al 2008

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

Costantini 2008, BMC Cancer

WHO ladder - is it effective?

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

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

WHO ladder in practice

http://www.drugdevelopment-technology.com/projects/licofelone/index.html


• 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


• 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!

Effectiveness of the ladder as a whole

....but first some questions about your practice

• 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’?


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


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 tooZech et al 1995 Pain


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


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

Evidence base for specific aspects


EAPC guidance

• European Association for Palliative Care

– Guidance on using strong opioids 1996• updated 2001

– 20 recommendations


EAPC guidanceWHO ladderWHO ladder EAPC guidanceEAPC guidanceBy the mouthBy the mouth oral route preferredoral route preferred

By the clockBy the clock start with normal release start with normal release before modified releasebefore modified release

By the ladderBy the ladder morphine preferred strong morphine preferred strong opioidopioid

methadone not methadone not recommended for non-recommended for non-specialistsspecialists

Individualised for patientsIndividualised for patients switch opioids if side effects switch opioids if side effects occuroccur


‘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


‘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

preparationsWiffen and McQuay 2007, Cochrane Database


‘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 InstWatanabe et al 2008


‘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


‘By the ladder’

• 2-step or 3-step ladder best?


‘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 stepsEisenberg 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 scaleStockler et al 2004, JCO


‘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 ManageMaltoni et al 2005 Supp Care Cancer






Individualised for patients switch opioids if side effects occur

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

• …..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

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

Morphine or fentanyl first?

• 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


‘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


‘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

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

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

• Thank you

• [email protected]

cancer pain management using evidence to support practice mike bennett professor of palliative...

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