EVIDENCE BASED MEDICINE AND CANCER PAIN THERAPY

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Cancer pain Neuropathic pain and
BTcP Sebastiano Mercadante, MD Director Anesthes
ia and Intensive Care Unit Pain Relief and
Palliative Care Unit La Maddalena Cancer Center
Palermo Italy Professor of palliative
medicine University of Palermo
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Cancer pain is complex

• 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

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

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Neuropathy induced by CH
Vinka-alkaloids (vincristine) Taxanes
(paclitaxel, docetaxel) Platinum (cis, carbo,
oxali-platinum) Thalidomide
Co-treatment, high cumulative
doses Prevalence10-100 Onset severity depend
on concomitant conditions diabetes, alcholism,
paraneoplastic
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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
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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
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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

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WHO analgesic ladder still alive?
Strong opioids Non-opioids NSAIDs adjuvants
Weak opioids Non-opioids NSAIDs adjuvants
Persisting pain
Non-opioids NSAIDs adjuvants
Uncontrolled pain
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Amitriptyline in neuropatic cancer pain in
patients on morphine therapy a R-C
studyMercadante et al, Tumori 2002
Adverse effects Drowsiness, confusion and
dry mouth, significantly increased
Analgesic effects No significant differences
in pain intensity were found in a cross-over
study, unless for worst pain
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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...
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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?
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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
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• Main conclusions
• Opioids alone can be effective in NP
• Best evidence for gabapentin
• Reduction on gt1 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 ?

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• 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
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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

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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
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Optimisation of the opioid regimenMercadante 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 regimen2
• Mostly same location as baseline pain
• Higher basal pain intensity more episodes
• Resistant pain related to the onset spontaneous
  recovery

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pain peaks
Well controlled pain
a
pain peaks
c
Uncontrolled pain
b
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
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Ideal Breakthrough Pain Medication

• Rapid onset
• Short duration of effect
• Minimal side effects
• Noninvasive, easy-to-use
• Cost-effective

Portenoy RK, Hagen NA. Pain. 199041273-281.
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BTP Profile
Pain relief gap
Pain Intensity
Oral Morphine Profile
BTP Profile
Overmedication
30
5
60
Time (minutes)
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Treating Cancer PainIdeal
Over Medication
Around-the-ClockMedication
Persistent Pain
Time
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Fentanyl

• 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.
200121397-400.2. Pereira J et al. J Pain
Symptom Manage. 200122672-687.
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BTcP Therapies Target Product Profile

• Concentrationtime profile that closely mirror
  the pain intensitytime profile of the BTcP
  episode
• Delivery systems with potential to
• Enhance dissolution
• Enhance absorption
• Minimize the first-pass effect

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BTcP Therapies Delivery Systems
1998
2009
2006/2008
2009
2008
2009
Oral trans-mucosal fentanyl citrateOTFC
FENTORA(US)/ EFFENTORA(EU)
ONSOLIS (US) FBSF
Rapinyl/ Abstral (EU) SLF
Instanyl (EU) INFS
Nasalfent (EU) FPNS
Oral Transmucosal Lozenge
Sublingual Fentanyl
Effervescent Buccal Tablet
Fentanyl Buccal Soluble Film
Intranasal Fentanyl Spray
Fentayl Pectin Nasal Spray
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BTcP Therapies Delivery Systems Cont.

• Buccal/Sublingual
• Actiq
• Effentora
• Onsolis
• Rapinyl/Abstral

• Intranasal
• Instanyl
• NasalFent

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BTcP Therapies Early Absorption parameters
Actiq Effentora Onsolis Abstral Instanyl Nasalfent
Dose (mcg) 400 100-1600 400 100-800 400 100-1200 400 100-800 400 50-200 400 100-800
Dwell Time (min) 15 15-20 N/A N/A
Cmax (ng/mL) 0.6 0.9 0.7 0.7 2.5 1.5
Tmax (min) 120 (30240) 45 (20240) 60 - - (23240) 15 (6-90) 20 (5-90)
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IV fentanyl Intranasal fentanyl
peak
Intravenous morphine
The rush. .. to meaningful pain relief A
question of minutes
Effervescent fentanyl
Sublingual fentanyl
peak
OTFC
Oral methadone
Oral morphine oxycodone hydromorphone
T0 T15
T30 T45
Mean duration of a BP event
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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
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• Portenoy RK, et al. Pain. 199979303-312.
• Christie JM, et al. J Clin Oncol.
  1998163238-3245.
• Farrar JT, et al. J Natl Cancer Inst.
  199890611-616.
• Coluzzi PH, et al. Pain. 200191123-130.

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Main concerns about OTFC studiesin 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 gt33
  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...

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Dose of breakthrough oral opioid versus ATC dose
from the four studies of OTFC Significant
relationship (plt0.001) High variability?
120 100 100 80 60 40 20 0
0 100 200 300 400
500 600 700 800
Hagen et al. J Palliat Med 2007
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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.
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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
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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

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

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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
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Conclusion

• BP should be separately evaluated
• Characteristics stressed
• Optimization of opioid therapy
• Double prescription specific as needed
• Choice according to timing and patients
  preference
• Selected cases require more expertise
• More data needed on new technologies

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Normal pain transmission

• Periphery
• There is transduction of alterations in the
  milieu via specialized receptors
• Transduction occurs via primary afferents (Aß,
  Ad,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