Physical aspects: type

Temporal relationship Acute pain Chronic pain Incident pain/break through pain Physiopathological mechanism Nociceptive pain
Somatic pain Deep Superficial Visceral pain

Neuropathic pain

Nociceptive pain

Pain transduction

Peripheral nociceptors

Peripheral nociceptors

Nociceptive pain: inflammation

Pain transmission

Nerve conduction

Pain perception

Anatomical changes: bone cancer pain model

Anatomical changes: bone cancer pain model

Schwei MJ et al. J Neurosci. 1999 10

Neurochemical-anatomical alterations: bone cancer pain model

11

Neuropathic pain

Neuropathic pain

Gilron, I. et al. CMAJ 2006;175:265-275 13

Treatment

Multidimensional approach
Physical aspects Nociceptive pain Neuropathic pain Psychological aspects Social aspects Spiritual aspect Multidisciplinary team involvement

15

Pain in cancer: temporal relationship

Acute pain Chronic pain Onset Cause Function Management Administration Side effects Well defined Determinable Warning Treatment Parenteral Acceptable Less well defined Less determinable None Prevention Oral/transdermal Unacceptable

16

Pain modulation
Interference with pain transduction Redrawal of traumatic factors Interference with mediators Interference with pain transmission Interference with pain perception

17

Endogeneous pain modulation

Ligand Dynorphin Enkephalin Endorphin Orphanin GABA Glycine Anandamide 5-hydroxytryptamine (HT) System Intraspinal Intraspinal Midbrain Midbrain Midbrain Intraspinal Intraspinal Intraspinal Bulbospinal Receptor -opioid receptor - and -opioid receptor -opioid receptor -opioid receptor GABA receptors Glycine receptors CB1 receptors 5-HT1b receptor 5-HT 3 receptor alpha2 receptors

Nor-epinephrine

Bulbospinal

18

Opioid receptor: transduction

Taylor et al. J Pharmacol Exp Ther. 2001

19

Opioid receptor: modulation

Taylor et al. J Pharmacol Exp Ther. 2001 20

Opioid receptor: modulation

21

Opioid receptor: modulation

Kumar et al, Cochrane Database Syst Rev. 2006 22

Opioid receptor: modulation by inflammation

Machelska, H. et al. Anesth Analg 2002 23

Opioid receptor: genetic variability

Klepstad P et al. Tidsskr Nor Laegeforen. 2005 24

Opioid receptor: physiological effects

-1 -2
Supraspinal analgesia Spinal analgesia Respiratory depression Cardiovascular depression Hypothermia Diuresis Anti-diuresis Nausea and vomiting Constipation Gastric emptying/acid secretion Euphoria Dysphoria Tolerance/dependency Convulsions/stress/shock x x x x x x x (x) (x) x x x x x (x) x

(x) (x) x x

x x (x) x

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Fundamental treatment principles

Pain Characteristics

Neuropathic Pain
Peripheral Central Dysesthesia Paresthesia Allodynia Hyperalgesia Hyperpathia Wind-up

Spontaneous Pain Evoked Pain Sensory Disturbances

Nociceptive Pain
Somatic Pain Superficial Deep Visceral Pain

Patient Characteristics
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Evaluation
Anamnesis Pain evaluation scales Numerical VAS Clinical examination Imaging

27

Neuropathic pain (DN4) questionnaire

28

Analgesics given regularly Appropriate medication for breakthrough pain Ready access to analgesic drugs By the easiest way Analgesics are given by the mouth/transdermal By the ladder Analgesics according to pain intensity Analgesic potency sequentially escalated along the analgesic ladder For the individual patient Adapted to the organ function/co-morbidity/age Careful and regular monitoring essential Additional medication for side effects
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Fundamental treatment By the clock principles

Analgesics: WHO pain ladder

30

Analgesics: level 1
Paracetamol Simplest and safest analgesic Mechanism of action not fully understand Central effect Indication
Nociceptive pain (Chemotherapy-induced) Neuropathic pain

31

Analgesics: level 1
Non-steroidal anti-inflammatory drugs Diverse group Main mechanism of action = reduction PG synthesis Ceiling analgesic effect Opioid dose-sparing effect Indications
Bone pain Inflammatory pain

32

Analgesics: level 2-3

Can be combined with level 1 medication Opioids Interact with opioids receptors Modulate pain transmission and pain perception Differ in Receptor activation Receptor affinity Solubility Body distribution Metabolites Administration

33

Opioids: receptor activation

Drug
Morphine Oxycodone Fentanyl Methadone Hydromorphone Buprenorphine Tramadol

Opioid receptor activation

A(1+2) A A(1) A A a a a A a a A a

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Opioids: receptor affinity

Drug Morphine Fentanyl Methadone Buprenophine Tramadol Low Affinity High + + +

+ +

35

Opioids: solubility
Drug Low Solubility Intermediate High

Morphine Oxycodone Fentanyl (L) Methadone (L) Hydromorphone (H)

+ +

+ +
+

36

Opioids: metabolism
Drug Codeine Oxycodone Morphine Hydromorphone Fentanyl Methadone Tramadol Metabolisation Metabolite CYP2D6 Morphine CYP2D6 UGT3B7 M3G-M6G UGT3B7 CYP3A4 CYP3A4 CYP2D6 (poor/rapid)

37

Opoids: resistance
limiting side effects Small group of patients Pathophysiology of true resistance Unknown Downregulation of number -receptors
Peripheral nerve damage Long-term use of opioids

Cholecystokinin (CCK)
Control of opioid sensitivity Cancer syndromes

De-activation of opioid-receptors
GIRK-receptor activation Inhibition of -receptor

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Analgesics: level 2
Codeine Weak opioid activity Tramadol Weak opioid activity Noradrenaline + serotonin uptake Buprenorphine No ceiling effect for analgesia Ceiling effects for side effects No restriction for future opioid use Additive effect when co-administered with morphine

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Analgesics: level 3
Morphine Still standard of care Hydromorphone 5x potent as morphine Fentanyl High potency (100x) High lipid solubility Oxycodone -opioid receptor Methadon -receptor agonist NMDA-antagonist Half-life: up to 190 hours Steady state: 6 - 12 hours of analgesia
Hydromorphone Morphine

Oxycodone

Fentanyl

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Adjuvant drugs
Medication Antidepressants Amitriptyline Anticonvulsants Carbamazepine Gabapentin Neuroleptics Haloperidol Benzodiazepines Diazepam Midazolam Anti-histaminics Diphenhydramine Psychostimulants Methylphenidate Indication Neuropathic pain Neuropathic pain Neuropathic pain Nausea, delirium, Oral dosing schedule 10-25 mg q 8h 200 mg q 12h 300 mg q 24-8h 2-5 mg q 8h pychosis, agitation

Anxiety, muscle spasm

Invasive procedures Pruritus, nausea

2-10 mg q 6-8h myoclonus 0.3-0.5 mg/kg (SC)

25-50 mg q 4-6h

Somnolence

5-15 mg q 8-12h

Kg: kilogram; mg: milligram; q: every; h: hours; SC: subcutaneously

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Antidepressants
Tricyclic antidepressants All products equally effective Use complicated by side effects Sedation! Steady state after 14 days! Start low - Go slow Amitryptilin 10 - 30 mg to start, increase until 50 - 75mg Increase every 5 to 7 days SSRI ? SNRI Duolextine promising in (diabetic) neuropathy No data in cancer pain

42

Anticonvulsants
Carbamazepine Interaction on Na+- channels (peripheral sensitization!) 200mg per day, every 3-4 weeks increase dose Inhibition of metabolism of TCA-drugs Serious side effects possible Gabapentine Structurally like GABA Ca2+-channel interaction (more central sensitization!) Safer pharmacological profile

43

Local anesthetics
Transdermal lidocaine patch 5%
Indications
Peripheral neuropathies Areas of sensory disturbances and/or pain Aching bone structures (vertebrae)

No systemic absorption Low incidence of skin reactions Rapid onset of analgesia No tolerance

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Combination of multiple drugs

Principles of pain control: multimodal analgesia

Different mode of action Additive or synergistic effect

Lower dose of each drug Less side effects

Which drugs?
Paracetamol NSAIDs Opioids (weak and strong) Ketamine 2-agonists Corticoids Local anesthetics

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Principles of pain control: mechanism-based treatment strategy Analgesic therapy

According to pathogenesis
Nociceptive
Superficial somatic Deep somatic Visceral

Pure neuropathic Mixed

Dominant mechanism of pain rather than intensity to determine sequence of analgesic therapy
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Principles of pain control: mechanism-based treatment strategy TREATMENT

Tumor Insult Dysfunction

Your Text here Mechanisms

Pathological

Clinical Symptoms

Disease State

Measurement

Clinical Syndrome

Based on the fact that various pathophysiologic types of pain have different sensitivities to distinct classes of analgesics 47

Principles of pain control: mechanism-based treatment Rational strategy polypharmacy

Antiepileptics
(Tricyclic) Antidepressants

in multidisciplinary team approach to control pain

NMDA CorticoReceptor steroids antagonists

Neuroleptics

Anti-agonists spasmotics

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Principles of pain control: mechanism-based treatment strategy

Pain Nociceptive Neuropathic Mixed Antidepressants + opioids Somatic Visceral Deep Peripheral

Deep

Superficial

Adjuvant anaglesics

Antidepressants

Local anesthetics Antidepressants Anticonvulsants

Opioids

Paracetamol NSAIF

Anticonvulsant

Anticonvulsants + opioids

Adjuvant analgesics

Opioids

Opioids

Opioids

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