Transcript Cancer Pain Epidemiology

Cancer Pain Diagnosis & Treatment
______________________________________________________________________________
Elon Eisenberg MD
Institute of Pain Medicine, Rambam Health Care Campus,
The Technion – Israel Institute of Technology, Haifa, Israel
Past
Cancer Pain Epidemiology
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 Half of the patients with cancer have pain at the time
of diagnosis
 Two thirds of patients with advanced cancer suffer
moderate to severe pain
Prevalence of Cancer Pain
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Tumor type
Stage
# of Studies
Prevalence
All
All
18
50 (11-75)
All
Advanced
33
71 (52-96)
Bone
Advanced
3-5
75 (70-85)
Pancreas
Advanced
3-5
79 (72-100)
Stomach
Advanced
3-5
75 (67-77)
Lung
Advanced
5
72 (58-85)
Breast
Advanced
3-5
72 (56-94)
Prostate
Advanced
3-5
70 (55-80)
Leukemia
Advanced
3-5
52 (5-58)
Adopted from Bonica 1990
Cancer Pain Etiology
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%
%
%
Cancer
Treatment
Unrelated
WHO Cancer Pain Treatment Guidelines
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WHO, 1986
The WHO “3-Step Analgesic Ladder”
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Non-Opioids
+Adjuvants
Weak-Opioids
+ Non-Opioids
+Adjuvants
Moderate
Mild
Pain Intensity
WHO, 1986
Strong-Opioids
+ Non-Opioids
+Adjuvants
Severe
Validation of the 3-Step Ladder
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
Experience gained by using the WHO Guidelines in the
treatment of 2118 patients over a 10-year period found
that "good" pain relief was reported by 76% of the
patients1.
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The application of the WHO analgesic regimen can
achieve pain relief in 90% of cancer patients2.
1.
2.
Zech et al., Pain. 1995
Colleau & Joranson. Cancer Pain 1998
Present
European Pain in Cancer (EPIC)
Israel Study Results Presentation
EPIC Steering Group Presentation
June 2007
© 2007
Research International. No part of these materials may
be used, reproduced or adapted without the prior written
consent of the copyright owner. All rights reserved
n=4947
Existence of Pain due to Cancer – Country Breakdown
More than two thirds of cancer patients report
pain which they attribute to their cancer
73
27
Total (n=4947)
95
5
Italy (n=457)
Sw itzerland (n=267)
9
Israel (n=269)
12
91
88
Czech Republic (n=282)
15
85
Norw ay (n=298)
17
83
Denm ark (n=337)
21
79
Rom ania (n=327)
21
79
UK (n=608)
23
77
France (n=642)
24
76
Base: all screened – (individual base sizes shown on chart)
S4. Have you suffered any pain due to your cancer?
61
39
Ireland (n=94)
Sw eden (n=1013)
64
36
Finland (n=353)
57
43
No pain
Pain
n=3066
Level of Pain per Country
Global mean score: 6.38
UK
 Sweden and
Norway are the
countries with
the lowest level
of pain
6.36
Swiss
6.5
Sweden
5.59
Romania
6.67
Norway
5.82
Italy
6.27
Israel
6.96
Ireland
6.1
France
6.72
Finland
6.52
Denmark
6.94
Czech Republic
6.11
4
5
6
7
8
 Israel is the
country where
the intensity of
pain is the
highest with 63%
of respondents
within the 7-10
range
Mean Level of pain
Base: all who currently experience pain once a month (n=3066)
S8. Thinking about the last time you experienced pain, please give me a number from 0 to 10 indicating the intensity of your pain where a “0” means
“no pain at all” and a “10” means “the worst pain imaginable”. ?
Classification of Cancer Pain
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Somatic
Visceral
Neuropathic
Headache and facial pain
Somatic Cancer Pain
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Visceral Cancer Pain
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Mixed Cancer Pain
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Cancer - Changing Epidemiology
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 The prevalence of cancer is increasing globally: an
estimated 17 million new cases projected for 2020
 But, there is cause for optimism: new treatment
options emerge, and old therapies are refined
 This have led to greater antitumor effects and
dramatic increase in survival rates.
Kanavos P. Ann Oncol. 2006
Cancer Pain - Changing Epidemiology
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 The evolution in the battle against cancer changes the way
patients experience cancer pain.
 In the past, the tumor was the underlying cause of pain for
most patients.
 Currently, treatment-related chronic pain syndromes are
being seen with greater frequency.
 Surgery, radiotherapy, chemotherapy, hormonal therapy and
other treatments, in combination or alone, have the potential
to lead to severe persistent pain states.
 These painful syndromes can seriously impair quality of life,
and may reduce adherence to potentially curative therapies,
leading to reduced survival.
Painful Syndromes Induced by Cancer Treatment
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 Chemotherapy induced painful neuropathies
 Chronic graft versus host disease
 Radiation induced painful syndromes
 Hormonal therapy and arthralgias
 Surgery induced painful conditions
Chemotherapy Induced Neuropathies
Platinum –
based drugs
Proteasome
inhibitors
Taxanes
Vinca
alkaloids
Other agents
Paice JA, Pain 2011
Chemotherapy Induced Painful Neuropathies
(CIPN)
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 Stocking >>> gloves
 Tingling, burning, painful numbness
 Typically dose dependent
 Onset during treatment; may escalate after final dose “coasting”
 Diagnosis: symptoms, examination, QST
 Mechanisms
 Mitochondial dysfunction
 Cytokine-induced inflammation
 Deficiency in neurotrophic factors
 Other?
Quantitative Sensory Testing (QST)
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Chemotherapy Induced Painful Neuropathies
(CIPN)
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 Prevention (neuroprotective agents, based on animal studies)
 Acetyl-L-carnitine
 Ethosuximide
 Olesoxime
 Treatment (like other types of neuropathic pain)
 Anticonvulsants
 Antidepressants
 Opioids
 Other agents
Chronic Graft Versus Host Disease (GVHD)
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 Patients with lymphoma, leukemia multiple myeloma
 Following allogeneic hematopoietic stem cell transplant
(SCT).
 Chronic GVHD affects 30-80% of patients who survive > 6
months after transplants
 Pain affects skin, mucous membranes and eyes
Treatment:
 Immunosuppression
 Topical steroids
 Topical estrogen
 Supportive treatment
Painful Signs & Symptoms of Chronic GVHD
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Paice JA, Pain 2011
Radiation Induced Painful Syndromes
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Paice JA, Pain 2011
Post Surgical Neuropathic Pain
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Intercosto-brachial nerve
Cancer Pain Treatment
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Radiotherapy
Chemotherapy
Hormonal Therapy
Surgery
Radio nucleotides
 Pharmacology
Non-opioids
Opioids
Adjuvant drugs
 Invasive procedures
 Physical therapy
 Psycho-social tx.
The WHO “3-Step Analgesic Ladder”
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Non-Opioids
+Adjuvants
Weak-Opioids
+ Non-Opioids
+Adjuvants
Moderate
Mild
Pain Intensity
WHO, 1986
Strong-Opioids
+ Non-Opioids
+Adjuvants
Severe
“3 Step Analgesic Ladder”?
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3
2
1
“3-Floor Analgesic Elevator”
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Simple Analgesics
Simple Analgesics
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•
•
•
•
•
•
Commonly used for mild pain
Add-on for moderate to severe pain
Paracetamol and dipyrone in Israel
Oral preparations
Ceiling dose
Increasing concerns (toxicity) with their use
NSAIDs & Coxibs
NSAIDs & Coxibs
FDA & EMEA
anouncments
“Doctors are advised to
use the lowest effective
dose for the shortest
possible duration of
treatment”
Opioids
Opioids in Cancer Patients
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Regard as: ‘Corner stone’ of cancer pain treatment
Use: the simplest route
Choose: the appropriate drug, dosing and intervals
Cover: both ongoing and breakthrough pain
Monitor: effectiveness & adverse effects
Reassess: as needed
Use the Simplest Route
Simplest Routes of Opioid Administration
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 For ongoing pain
 Oral
 Transdermal
 Rectal (rarely)
 For breakthrough pain
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Transmucosal
Oral
Buccal*
Transnasal*
 I.V or S.C. in rare cases (AE’s, NPO)
 Avoid I.M. injections
Choose the Right Drug
Opioids for Mild to Moderate Pain
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 Codeine
 Tramadol
 Buprenorphine
Codeine
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Opium alkaloid
1/10 as potent as morphine
Oral analgesic dose >30 mg
Bioavailability- 40%
Inactive metabolite: codeine-6-glucuronite
Transformation to morphine: 2% - 10% (CYP 2D6)
Alone or in combination with paracetamol ± caffeine
(Cod-acamol, Rokacet)
Tramadol
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Not regarded as an opioid (stigma, prescriptions)
30% binding to opioid receptors
Blocks reuptake of norepinephrine and serotonin
Oral (injectable) formulations
Maximal oral daily dose: 400 mg
Sustained release-tabs; immediate release-drops/flashtabs
AEs: CNS, nausea
Tramal;Tramadex
Types of Opioids
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100
Agonist
Partial agonist
Agonist-antagonist
Response
80
60
40
20
0
Dose (mg)
Buprenorphine
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Partial  agonist,  agonist,  antagonist
Not reversed by naloxone
New once weekly transdermal formulation
No dose adjustments in elderly patients or impaired renal
function
 Dose not increase bile and pancreatic ducts pressure
 Can be used together with other short-acting opioids
 Nausea and vomiting are common side effects
(Butrans patch 5,10, 20 µg/h); maximal daily does 40µg/h
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Opioids for Moderate to Severe Pain
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Morphine
Oxycodone
Fentanyl
Methadone
Meperidine
Morphine
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 Well known, available
 Multiple routs of administration (p.o.; p.r; s.c.; i.m.;
i.v.; epidural; i.t.)
 Easy to titrate
 Metabolites:
 M6G- analgesia, nausea, respiratory depression
 M3G- inactive
 M6G (but not morphine) accumulates in renal failure
 Oral:parenteral analgesic ratio = 3:1
Oxycodone
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Does not have the ‘morphine stigma’
 and possibly weak  agonist
Oral formulations only
Bioavailability 60% (morphine 30%)
Accumulates in renal failure
Immediate and sustained release
Safely profile similar to morphine
(Oxycod, Oxycontin, Percocet)
 Available as oxycodone/naloxone combination
(Targin)
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Fentanyl
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µ opioid receptor
100 times more potent than morphine
Lipid soluble (Transdermal, transmucosal)
Transdermal:
 Steady plasma levels for up to 72h
 Delayed onset of analgesia
 Hard to titrate
 Skin and ambient temperature may change absorption
 Does not accumulate in renal failure patients
(Durogesic; Fenta)
Fentanyl
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 Transmucosal (OTFC, FBT)
 For breakthrough cancer pain
 Quick onset of analgesia
 Short duration of action
 Does not accumulate in renal failure patients
 Limited number of daily units (in Israel)
(Actiq)
Methadone
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Oral and epidural routs
Cheap
Good analgesia (NMDA receptor antagonists)
Does not accumulate in renal failure
‘Bad’ stigma
Not available everywhere
Variable duration of analgesia (usually x3/day)
Titration once weekly
Complicated conversion ratios
Suggested Morphine-Methadone
Conversion Ratios
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morphine dose
<100 mg
100-300mg
300-600mg
600-800mg
morphine: methadone
3:1
5:1
10:1
12:1
Choose the Right Dose
Choose the Right Dose
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The right dose is the effective dose
Most opioids have no maximal dose
Large inter-individual differences in dosage
Dose adjustments should be made rapidly
(daily/hourly)
Under / over treatment should be avoided
Relative potency should be considered when one
opioid is replaced by another (opioid rotation)
Relative Potency of Opioids
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Morphine
Codeine
Meperidine
Tramadol
Oxycodone
Methadone
Buprenorphine
Fentanyl
1
1/10
1/8
1/5
1.5-2
5-10
60
100-150
Choose the Right Interval
Plasma Half-Lives of Opioids (hours)
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Morphine
Codeine
Oxycodone
Fentanyl
Methadone
Meperidine
Buprenorphine
2-3.5
3
3.5
3.5 (transdermal-22)
24
3-4
3
Dosage and Interval
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Over treatment
Therapeutic window
Under treatment
6
12
18
Time
24
Treat Breakthrough Pain
Constant and Breakthrough Pain
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100
80
VAS
60
40
20
0
Time in the day
Monitor adverse effects
Opioids Adverse Effects
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Common
 Constipation
 Nausea
 Sedation
 Confusion (delirium)
 Unsteadiness
Uncommon
 Urinary retention
 Myoclonus
 Pruritus
 Sweating
 Respiratory depression
 Psychological dependence
 OIH
Treatment of Opioid Side-Effects
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Reduce dose if possible
Add specific treatment
(constipation, nausea, sedation)
Consider “opioid sparing effect”
Consider “opioid rotation”
Consider alternative routes or treatments
Opioids in Cancer Patients
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 Tolerance
Rare
 Physical dependence
Yes
 Psychological dependence (Addiction)
Rare!!!
Adjuvant Drugs for Cancer Pain
Treatment
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Steroids
Antidepressants
Anticonvulsants
NMDA receptor antagonists
Mainly for neuropathic pain
Invasive Procedures for Cancer Pain
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Indications in 15%-20% of patients with cancer pain due to:
 Lack of efficacy of simpler methods
 Intolerable adverse effects
Cancer Pain Treatment
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Non-Opioids
+Adjuvants
Weak-Opioids
+ Non-Opioids
+Adjuvants
Strong-Opioids
+ Non-Opioids
+Adjuvants
III
II
I
Pain Intensity
Invasive procedures
+ Strong-Opioids
+ Non-Opioids
+Adjuvants
IV
Invasive Procedures for Cancer Pain
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Techniques
 Nerve blocks
 Spinal opioids
Nerve Blocks
Nerve Blocks
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Somatic
Sympathetic
Somatic Nerve Blocks (Anesthetic)
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 Local anesthetic ± steroids
 ‘Single shot’
 Continuous blocks (pleural, brachial plexus) for days to
weeks
 Rarely lytic
 AE’s: sensory loss, motor weakness, infection
Somatic Nerve Blocks (Lytic)
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Neurolysis by ethanol phenol or RF
Sensory nerves
Relief duration: weeks to months
Risks:
 prolonged sensory loss
 permanent paralysis
 anesthesia dolorosa
Somatic Nerve Block
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Post-Thoracotomy Pain Syndrome
Neurolytic Celiac Plexus Block
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Neurolytic Celiac Plexus Block
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Meta-analysis: Pain relief according to f/u duration
Duration
<2w c+p
<2w c
2-12w c+p
2-12w c
>12w c+p
>12w c
Studies
18
10
7
7
4
4
Patients
976
268
273
273
49
49
Eisenberg et al., Anesth & Anal 1995
% response
89
58
89
51
90
56
95% CI
87-91
52-64
85-92
45-57
78-96
41-70
Spinal Opioids
Spinal Opioids
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 Introduction of small quantities of opioids in close
proximity to their receptors
 High spinal opioid concentration
 Combination of opioids and other agents (admixtures)
 Profound analgesia with reduced opioid adverse effects
Spinal Opioids
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Techniques
 Epidural
 Intrathecal
Spinal Opioids
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Epidural
 Localized pain
 Opioids plus other agents
 ‘Open systems’
 Temporary systems
Spinal Opioids
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Intrathecal
 Diffuse pain (below the head)
 Opioids plus other agents
 Open and close systems
 Permanent systems (IDDS)
IDDS Versus Comprehensive Medical Management
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202 patients with cancer pain
VAS > 5
200 mg of oral morphine or more
Randomization:
 Comprehensive pain management
 Implantable intrathecal drug delivery system
 Outcome: pain, toxicity (4 weeks) and survival (6 months)
Smith et al., Clin Oncol 2002
.
IDDS Versus Comprehensive Medical Management
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Group
Intrathecal (n=71) Medical (n=72)
Pain type
Mixed (60%)
Mixed (60%)
VAS (initial)
7.6
7.8
Initial morphine (mg)
260
280
toxicity score (initial)
7.2
6.3
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VAS (end)
Pain reduction
toxicity score
toxicity score reduction
6 months survival
Smith et al., Clin Oncol 2002
3.7
(52%)
3.6
(17%)
(54%)
4.7
(39%) p=0.55
5.3
(50%) p<0.004
(37%) p<0.004
IDDS - Complications
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Drug induced adverse effects
Opioid tolerance
Intrathecal granuloma
System related complications (migration, infection)
Invasive Procedures for Cancer Pain
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 Invasive procedures are complementary to other
treatments
 Risk / benefit ratio should always be evaluated
 Not a panacea, but should always be considered as a
treatment option for moderate to severe pain
Pain can be effectively
treated in the majority of
patients with cancer
Thank You