Cancer pain management Using evidence to support practice
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Cancer pain management
Using evidence to support practice Mike Bennett
Professor of Palliative MedicineLancaster University
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Cancer pain epidemiologyCancer pain epidemiology
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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
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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
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• 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
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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
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Proportion of cancer patients in the weeks preceding death who were prescribed analgesics (N=234)
Borgsteede et al 2008
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Proportion of non-cancer patients in the weeks preceding death who were prescribed analgesics (N=188)
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Costantini 2008, BMC Cancer
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WHO ladder - is it effective?
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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
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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
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WHO ladder in practice
• 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
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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!
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Effectiveness of the ladder as a whole
....but first some questions about your practice
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• 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’?
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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
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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 tooZech et al 1995 Pain
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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
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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
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Evidence base for specific aspects
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Evidence base for specific aspects
EAPC guidance
• European Association for Palliative Care
– Guidance on using strong opioids 1996• updated 2001
– 20 recommendations
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Evidence base for specific aspects
EAPC guidanceWHO ladderWHO ladder EAPC guidanceEAPC guidanceBy the mouthBy the mouth oral route preferredoral route preferredBy the clockBy the clock start with normal release start with normal release
before modified releasebefore modified releaseBy 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
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Evidence base for specific aspects
EAPC guidanceWHO ladderWHO ladder EAPC guidanceEAPC guidanceBy the mouthBy the mouth oral route preferredoral route preferredBy the clockBy the clock start with normal release start with normal release
before modified releasebefore modified releaseBy 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
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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
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Evidence base for specific aspects
EAPC guidanceWHO ladderWHO ladder EAPC guidanceEAPC guidanceBy the mouthBy the mouth oral route preferredoral route preferredBy the clockBy the clock start with normal release start with normal release
before modified releasebefore modified releaseBy 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
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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
preparationsWiffen and McQuay 2007, Cochrane Database
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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 InstWatanabe et al 2008
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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
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Evidence base for specific aspects
EAPC guidanceWHO ladderWHO ladder EAPC guidanceEAPC guidanceBy the mouthBy the mouth oral route preferredoral route preferredBy the clockBy the clock start with normal release start with normal release
before modified releasebefore modified releaseBy 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
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Evidence base for specific aspects
‘By the ladder’• 2-step or 3-step ladder best?
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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 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
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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 ManageMaltoni et al 2005 Supp Care Cancer
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Evidence base for specific aspects
EAPC guidanceWHO ladderWHO ladder EAPC guidanceEAPC guidanceBy the mouthBy the mouth oral route preferredoral route preferredBy the clockBy the clock start with normal release start with normal release
before modified releasebefore modified releaseBy the ladderBy the ladder morphine preferred strong morphine preferred strong
opioidopioid
methadone not methadone not recommended for non-recommended for non-specialistsspecialists
Individualised for patients switch opioids if side effects occur
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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
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• …..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
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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
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Morphine or fentanyl first?
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• 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
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Evidence base for specific aspects
EAPC guidanceWHO ladderWHO ladder EAPC guidanceEAPC guidanceBy the mouthBy the mouth oral route preferredoral route preferredBy the clockBy the clock start with normal release start with normal release
before modified releasebefore modified releaseBy 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
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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
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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
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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
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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