CANCER PAIN

The Important Role of Cancer Pain Mechanism

and Assessment

YUDIYANTA
PAIN DIVISION
DEPT OF NEUROLOGY
FACULTY OF MEDICINE, PUBLIC HEALTH AND NURSING
UNIVERSITAS GADJAH MADA/ DR SARDJITO GENERAL HOSPITAL
YOGYAKARTA, INDONESIA
Definition
• Cancer pain is: the pain that is caused by tumor progression, and related
pathological processes, invasive procedures, toxicities of treatment, infection
and physical limitation (Reddy SN, 2015)
 DURING CANCER Tx
CANCER PAIN PREVALENCE
No Pain
45% AFTER CURATIVE TX
Pain
55% ADVANCED, METASTATIC, OR TERMINAL
Pain
39%

No Pain
No Pain
61%
34%

Pain
66%

van den Beuken-van Everdingen et al. Update on Prevalence of Pain in Patients With Cancer: Systematic Review and Meta-Analysis; J Pain Symptom Manage 2016;51:1070-1090
The Important Role of Cancer Pain Mechanism
and Assessment

• A mechanism-based approach in pain therapy is essential for providing a

more individualized and effective analgesia

• Special approach  important to recognize and classify the underlying

pathophysiological processes.
Objectives
1. Cancer Pain Mechanism
2. Cancer Pain Assessment
Objectives
1. Cancer Pain Mechanism
2. Cancer Pain Assessment
 3

1
2
 Cancer Pathophysiology Of Cancer Pain
(Rai & Vernucci, 2018)

Tumor Microenvironment 1. Invasion

2. Migration
1. Low pH 3. Metastases
2. Hypoxia
3. Altered anabolism & catabolism/
anaerobic metabolism
4. Inflammation and Pain mediators

Chronic Cancer Pain

 Cancer Pathophysiology Of Cancer Pain
(Rai & Vernucci, 2018)

Tumor Microenvironment 1. Invasion

2. Migration
3. Metastases
1. Neural invasion
2. Bone Matastasis

• Cox • Increased Intraosseus pressure

• Nerve root infiltration
• Nerve compression
• SMP
• Microfracture
• Periosteum stretching
• Muscle spasm
• Osteoclastic bone resorbsion
• Peripheral & central pain
sensitization

Chronic Cancer Pain

 Cancer Pathophysiology Of Cancer Pain
(Rai & Vernucci, 2018)

Tumor Microenvironment 1. Invasion

2. Migration
1. Low pH 3. Metastases
2. Hypoxia 1. Neural invasion
3. Altered anabolism & catabolism/ 2. Bone Matastasis
anaerobic metabolism
4. Inflammation and Pain mediators
• Cox-2 • Increased Intraosseus pressure
• Nerve root infiltration • Muscle spasm
• Nerve compression • Osteoclastic bone resorbsion
• SMP • Peripheral & central pain
• Microfracture sensitization
• Periosteum stretching

Chronic Cancer Pain

Mechanism-Based Classification of Cancer Pain
1. Central sensitization/central neurogenic mechanism/central nociceptive
mechanism (Neuropathic)
2. Peripheral sensitization/peripheral neurogenic mechanism (Neuropathic)
3. Sympathetically maintained pain/sympathetically dependent pain
mechanism (Neuropathic)
4. Peripheral nociceptive mechanism (Nociceptic)
5. Cognitive-affective mechanism (Nociplastic)
 Cancer Pathophysiology Of Cancer Pain
(Rai & Vernucci, 2018)

Tumor Microenvironment 1. Invasion

2. Migration
1. Low pH 3. Metastases
2. Hypoxia 1. Neural invasion
3. Altered anabolism & catabolism/ 2. Bone Matastasis
anaerobic metabolism
4. Inflammation and Pain mediators
• Cox-2 • Increased Intraosseus pressure
• Nerve root infiltration • Muscle spasm
• Nerve compression • Osteoclastic bone resorbsion
• SMP • Peripheral & central pain
• Microfracture sensitization
• Periosteum stretching

Chronic Cancer Pain

Ca Related pain Ca Associated pain Tx-related pain Ca Independent pain

• Localized, poorly-localized, referred pain • Decreased immunity (HZV) • Pain due to surgery, • Due to presence of
• Pressure effect on organs/nerves • Back pain in prolonged Chemotx, Radiotx, Dx the other chronic
• Infiltration bed rest procedures disease at the time of
• Metastasis diagnosis
Objectives
1. Cancer Pain Mechanism
2. Cancer Pain Assessment
 Assessment in Cancer Pain

Disease of Cancer Assessment of Ca Pain

History

Physical Examination

Additional Examination

Diagnosis of Cancer

Menejemen of Cancer
(NCCN Guideline)
Surgery, Radio-tx, Chemo-tx, Immuno-Tx
TERAPI FARMAKOLOGI UNTUK NYERI KANKER
 Assessment in Cancer Pain

Assessment of CANCER Assessment of CANCER Pain

Onset of Type Intensity SAFETY & Generator

Pain of Pain of Pain Comorbidity of Pain

Acute Chronic
< 3mo > 3mo
 Assessment

Assessment of Disease Assessment of Cancer Pain

Onset of Pain Type of Pain Intensity of Pain SAFETY & Comorbidity Generator of Pain

Nociceptic Neuropathic Nociplastic

Pathophysiology
Somatic Visceral Peripheral Central Central SFN/
Sensitization Physiciatric
OF PAIN
SMP
Syndrome

Screening Tools: Pain Detect, LANSS, ID Pain, DN4, STEPs,

Symptomatology
Physical Examination
Confirmation Test
GeneralTreatment Modality
Nociplastic Pain STRESS OR Chronic opioid use

Activation of Symphatetic Nervus System

Hypothalamus
CRH
Pituitary
OPIOID Induced Hyperalgesia ACTH
Adrenals

Glucocorticoid
Cathecolamines

Imune System Muscle Liver Fat Cells Heart Rate

Inflamation Metabolism Gluconeogenesis FFA Mobilitiation

Sleep
Anxiety
Widespread Pain Fatigue Stiffness Muscle Microcirculation
Disturbance & Hypoxia
 Assessment

Assessment of Disease Assessment of Cancer Pain

Onset of Type Intensity SAFETY & Generator

Pain of Pain of Pain Comorbidity of Pain

Mild Moderate Severe

Pain Intensity Scael: VAS, NPS, VS, WB,

FLACC, Comfort Scale, PAINAD etc
Physical Examination

Confirmation Test

Dose, Route
 Assessment

Assessment of Disease Assessment of Cancer Pain

Onset of Type Intensity SAFETY & Generator

Pain of Pain of Pain Comorbidity of Pain

Comorbidity Side Effect Alergy

CCV GI Renal Respiratory Yellow Flags

Hystory

Physical Examination
Confirmation Test

Specific Treatment Modality

Pain Yellow Flags
 Assessment

Assessment of Disease Assessment of Pain

Type of Pain Intensity of Pain SAFETY Generator of Pain

Topical Diagnosis of Pain

Hystory

Physical Examination

Confirmation Test
Interventional Pain Management
Generator of Pain:
Syndromic Classification Of Pain Caused Directly By The Solid Tumor

• Neoplastic damage to bone and joints (35%)

• Neoplastic damage to viscera (33%)
• Neoplastic damage to soft tissue and miscellaneous (45%)
• Lesions of Nervous Tissue (34%)

Caraceni & Skhkodra, Cancer Pain Assessment And Classification, 2019

Kumar Senthil P, Cancer pain: A critical review of mechanism-based classification and physical therapy management in palliative care, 2011
 Re-assessment In Analgesic Treatment
• Oral route of administration of analgesics should be advocated, unless
contraindicated
• “Five A’s” should be regularly assessed:
1. Analgesic response and breakthrough pain
2. ADL
3. Adverse effects of the treatment regimen
4. Aberrant behaviours.
5. And the use of adjuvant
• Opioid detoxication is necessary  gradually elicit opioid withdrawal symptoms
(usually no more than 20% to 25% dose reduction every 2 days)

Fallon M,, et al. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines†. Ann Oncol. 2018;29(Supplement_4): iv166-iv191.
Davis MP. Cancer Pain. In: The MASCC Textbook of Cancer Supportive Care and Survivorship. ; 2011:11-22.
 "the transient exacerbation of pain occurring in
40-86%
a patient with otherwise stable, persistent pain"
 GENERAL TREATMENT MODALITY

PAIN

Non Pharmacology Pharmacology Interventional PM Surgery

Neural Blockade Stimulatory Technics

Psychologic Tx Rehabilitative App.
Neurolytics Medication Pump

Pure Analgetics NSAIDs Adjuvant Analgetics Opioid Anestetic

Anti- Vitamins?
PCT Convulsant
Metampiron
Anti- Steroids
Ns NSAIDs Coxib Deppresant Opioid Atypical Opioid
Conclusion

• Optimal pain management starts from optimal pain

assessment

• Treatment should be comprehensive: underlying

etiologies and cancer pain
PHARMACOLOGY CONTROLLING
CANCER PAIN WITHOUT OPIOD
Dessy R Emril
Pain and Headache Division
Neurology department, medical Faculty
Universitas Syiah Kuala
 • Untreated cancer pain is a human disaster
• not unlike famine; its victims are starving for relief.”

• Ronald Piana
• The New York Times
• October 1, 2014
 INTRODUCTION
• The neurophysiology of cancer pain is complex; it involves;
• inflammatory,
• neuropathic,
• ischemic, and
• compression mechanisms at multiple sites
• Knowledge of these mechanisms and the ability to decide if a
pain is nociceptive, neuropathic, visceral, or a combination
of all three will lead to best practice in pain management.
* Prevalence of the Most Common Symptoms in
Advanced Cancer (1000 Adults)
Symptom % Symptom %
Pain 82 Lack of Energy 59
Easy Fatigue 67 Dry Mouth 55
Weakness 64 Constipation 51
Anorexia 64 Dyspnea 51
>10% Wt Loss 60 Early Satiety 50

Donnelly and Walsh

Semin Oncol, 1995
 * Incidence Of Cancer Pain

• 50 % of all cancer patients

• 70-80 % of all advanced cancer patients
• 50 % will have moderate to severe pain
• 30 % will have severe pain
 Barriers to Optimal effective Cancer Pain Treatment
• PAIN ASSESSMENT
• The main barrier to optimal effective pain relief is inadequate assessment of pain.
• Pain assessment should take place at regular intervals, following the start of any
new treatments and at each new report of pain.
• Patients with cancer may have a number of fears about their pain and might be
reluctant to report pain. Pain control can be enhanced if management strategies
include interventions on relieving anxiety and depression.
• Pain and its management should be discussed with the patients and their
families. Patients with cancer pain should be encouraged to be active participants
in the management of their own pain.
Pain Assessment:

• Intensity
• Etiology
• Type
• medication
 Etiology of Pain in Cancer Patients
• Not every type of pain in a patient with cancer is related to
the tumor and, as a result, not every type of pain perceived
by oncological patients can be considered and defined
automatically as cancer pain.

• Therefore, in oncological patients presenting with pain, it is

very important to specify if the pain perceived is caused by
the tumor, related to treatments or to other comorbidities,
in order to be able to provide the necessary treatment.
 Cancer Related Pain
Causes related Treatment Related

- Infection – surgery,
- Tumor related -radiation therapy,
- Nervous system -chemotherapy
- bone -interventional
- visceral procedures
- mucosal
 TYPE OF CANCER PAIN

•Nociceptive/inflamatory pain
•Neurophatic pain
•Mixed pain
•Bone pain
 *WHO Ladder Principles
The five essential concepts in the WHO approach to
drug therapy of cancer pain are:

By the type
By the Etiology
By the mouth
By the clock
By the ladder - intensity
For the individual
With attention to detail
 OPIOID FOR CANCER PAIN
• Today, opioids are still the cornerstone of CP
treatment.
• However, their role in treatment has been evolving,
largely due to a growing understanding of their
adverse effects associated with chronic use
• Prolonged opioid use may lead to the development of
tolerance, hyperalgesia, dependency, or addiction.
• Many cancer patients and cancer survivors require
chronic opioid therapy (COT) (defined as greater than
three months) which has been associated with increased
risk of
• endocrinopathies,
• depression,
• sleep-disordered breathing,
• impaired wound healing,
• substance use disorders, and
• cognitive impairment
 Nociceptive pain in cancer Pain

• Patients affected by hematological cancer revealed

different pain syndromes :
• 56% diagnosed as deep somatic,
• 15% as superficial somatic,
• 14% as visceral,
• 7% as neuropathic, and
• 8% mixed
• Caraceni A, Shkodra M. Cancer Pain Assessment and
Classification. Cancers (Basel). 2019;11(4):510.
Published 2019 Apr 10. doi:10.3390/cancers11040510
• The combination of NSAID and step III opioids
showed a beneficial effect,
• Non-steroidal anti-inflammatory drugs,
Not include
flupirtine, and dipyrone can be recommended the Anti
for the treatment of cancer pain either alone or
in combination with strong opioids.
Convulsant
• The use of acetaminophen in the palliative and anti
setting cannot be recommended
• There is a lack of evidence regarding pain
Depresant,
treatment by non-opioids in specific cancer yet
entities.
 Why carry out
this study?
• While opioids have long been a
potential role of cyclooxygenase
(COX) inhibitors in the primary
prevention of malignancy,
reducing metastatic spread and
improving overall mortality
mainstay of cancer pain control,
advances in the field of pain
management have shown that
exclusive use of opioids to treat
pain is no longer necessary.
There is a large movement
toward the use of multimodal
analgesia to treat pain, which
has decreased opioid
consumption and increased
patient outcomes.
There is no high‐quality evidence to
support or refute the use of NSAIDs
alone or in combination with opioids for
the three steps of the three‐step WHO
cancer pain ladder. There is very
low‐quality evidence that some people
with moderate or severe cancer pain can
obtain substantial levels of benefit within
one or two weeks.

The current World Health Organization
guidance is not to start corticosteroids, but
there is no robust evidence of risk in patients
with cancer and coronavirus disease 2019. A
risk-benefit analysis should be performed for
each patient on the use of steroids in cancer
care
Corticosteroids are widely used in the
management of urological cancers, and are
broadly given at either physiological or
supraphysiological doses. Physiological
doses of corticosteroids are effective as a
second-line hormonal treatment for
metastatic castrate-resistant prostate cancer
with prostate-specific antigen response
rates to 0.5 mg of dexamethasone daily of
over 40% [5]. Prednisolone at 5 mg twice
daily is effective at preventing the
hypermineralocorticoid dose-limiting
toxicity of abiraterone, a life-prolonging
CYP-17,20-lyase inhibitor., and nausea.
 NEUROPHATIC PAIN CANCER PAIN

‘New’ types of cancer

Standard’ cancer
neuropathic pain
- Direct invasion and damage
- Para-neoplastic neuropathies
related neuropathic pain
Post chemotherapy
Axonal degeneration and demyelination
Cancer Induced Bone Pain (CIBP)
Unique state with inflammatory and
neuropathic elements
 Aetiology of pain in cancer patients

Aetiology of pain in cancer patients

All cancer pain Neuropathic pain patients
patients* only**

Direct effect of cancer 76% 64%

Cancer treatment 11% 20%

Indirect effects 5% 4%
Co-morbid conditions 8% 12% *Grond et al, 1996
**Bennett et al 2012
 Assessment
• Neuropathic pain mechanisms and symptoms exist as a
spectrum
• especially in advanced cancer
• mix of inflammatory and neuropathic mechanisms

• More useful to ask yourself

• ‘is this pain more or less neuropathic?’
• ‘does this patients have pain of predominantly neuropathic origin?
 Screening tool performance
in neuropathic cancer pain
• LANSS, DN4, pain DETECT

• Much lower scores for definite NP compared to non-

cancer populations
• Sensitivity = 30-58% [normally 75-85%]

Mercadante et al 2009
Paredes et al 2011
Rayment et al 2011
DRUG Baseline End Mean change

Amitriptyline 7.8 3.2 4.6

Gapapentin 7.5 3.1 4.4

Pregabalin 7.8 2.5 5.3

Placebo 7.5 3.4 4.1

THE EFFECTIVENESS OF ANTI-NEUROPATHIC PAIN
IN CANCER PAIN PATIENTS IN DR. ZAINOEL ABIDIN
GENERAL HOSPITAL BANDA ACEH

Correspondence : dessyemril@unsyiah.ac.id
*Dessy R. Emril and Laila Fajri
Department Of Neurology, Faculty Of Medicine, Universitas Syiah Kuala,
Dr. Zainoel Abidin General Hospital, Banda Aceh, Indonesia
Saturday 7 December, 2019
 Type of pain in cancer pain patients

Type of Pain Frequenc Relative

(DN-4) es (n) Frequences (%)
Neuropathic 50 70.4
Nociceptive 21 29.6

Total 71 100.0
 Pain Scale in Type drugs used and combination
(Paired -T Test)
Type of drugs Mean Sig. (2 -Tailed)
Gabapentin
Pre 7.7778 0.000
Post 3.3333
Gabapentin + Opioid
Pre 8.5000 0.000
Post 3.6667
Gabapentin + Opioid + NSAID
Pre 8.6667 0.013
Post 3.6667
Gabapentin + Opioid + Paracetamol
Pre 8.8000 0.000
Post 3.4000
Gabapentin + Paracetamol
Pre 7.8000 0.006
Post 2.4000
Opioid
Pre 7.1111 0.000
Post 4.6667
Opioid + NSAID
Pre 7.8889 0.000
Post 4.4444
Opioid + NSAID + Paracetamol
Pre 6.6000 0.001
Post 4.2000
Opioid + Paracetamol
Pre 8.2000 0.000
. Comparation of Pain Reduction for each Type of Analgetic Drugs
(One - Way ANOVA Test)
Type of Drugs N Mean SD P-Value
Gabapentin 9 4.4444 0.88192

Gabapentin + Opioid 6 4.8333 1.32916

Gabapentin + Opioid + NSAID 3 5.0000 1.00000

Gabapentin + Opioid + Paracetamol 5 5.4000 0.89443

Gabapentin + Paracetamol 5 5.4000 2.30217

0.000
Opioid 9 2.4444 1.23603

Opioid + NSAID 9 3.4444 1.66667

Opioid + NSAID + Paracetamol 5 2.4000 0.54772

Opioid + Paracetamol 20 2.6000 1.63514

Total 71 3.5915 1.77746

Comparation of Pain Reduction for each Type of Analgetic
Drugs (Post Hoc Duncan Test)
Type of Drugs N Pain Reduction (α = 0.05)
1 2
Opioid + NSAID + Paracetamol 5 2.4000

Opioid 9 2.4444

Opioid + Paracetamol 20 2.6000

Opioid + NSAID 9 3.4444

Gabapentin 9 4.4444

Gabapentin + Opioid 6 4.8333

Gabapentin + Opioid + NSAID 3 5.0000

Gabapentin + Opioid + Paracetamol 5 5.4000

Gabapentin + Paracetamol 5 5.4000

Sig. 0.256 0311

 CANCER INJUCED BONE PAIN (CIBP)
• CIBP is understood as a complex pain state with nociceptive but also
inflammatory and neuropathic characteristics
• Bone periosteum, bone marrow, and also bone matrix are highly
innervated tissues that contain a network of both sensory and
sympathetic neurons
• Given the biology of bone pain, the use of adjuvant analgesics, such
as gabapentinoids, seems prudent as many patients with CIBP have
neuropathic features
• Gabapentin blocks the process of central sensitization most likely by
modifying activation of the spinal microglia and release of pro-
inflammatory cytokines, which enhance pain transmission .
• In a small series, gabapentin has been shown to reduce breakthrough
pain caused by bone metastasis
 Cancer Therapy-Induced Pain
• Chemotherapy-induced neuropathies have illustrated the diverse and
unique nature of damage including taxol interruption of microtubular
aggregation, accumulation in dorsal root ganglia, and activation of a
neuro-immune reaction which may account for the side effects of
taxols
• Anti neuropatik pain golongan antikonvulsan, tidak termasuk ke
dalam kelompok Adjuvan (lag). Karena :
• 1. perasn antikonvulsan sdh tidak bersifat mayoritas
• Penggunaan sat ini HANYA untuk nyeri neuropatik
• Antinduropatik pain tidak tyermasuk ke DALAM gol adjuvan pada Step ledder
WHO, melainkan sebagai golongan tersendiri

• Non opiood, Antineuropatik npain, adjuvan (buat animasi step ledder WHO
USING OF ANTI CONVULSANT ACCORDING TO THE TYPE
ONF CANCER PAIN
NSAIDS,
NOCICEPTIVE/INGFLAMATORY PAIN
STEROID

NEUROPHATIC PAIN
MIXED PAIN ANTICONVULSANT
BONE PAIN (CIBP) PRGABALIN/GABAPENTIN
 STEP 3
Strong Opioid
for severe pain, terminal stage
(e.g morphine)
(NEW)TREATMENT LEDDER Anti convulsant
+/- Adjuvant

STEP 2
Weak opioid
for mild to moderate pain
(Tramadol)
+/- Non-opioid
Anti convulsant
+/- Adjuvant

STEP 1
Non-opioid
NASID, Steroid,
paracetamol)
Anti Convulsat FREEDOM FROM PAIN
+/- Adjuvant
 CONCLUSIONS
• The main barrier to optimal effective pain relief is
inadequate assessment of pain, THEREFORE Pain assessment
should take place at regular intervals, following the start of
any new treatments and at each new report of pain.

• ANTI CONVULSANT (Pregabalin) takes the important role in

the management of cancer pain and can be used in any steps
and type of cancer pain
THANK YOU