疼痛機制 the mechanism of pain

From Signal to Sufferings

從電氣訊號到疼痛

台大麻醉科孫維仁醫師

千古艱難惟一死..

是愛撫？還是懲罰？

疼痛處理不當，會怎樣？

疼痛處理得當，會怎樣？

Dilemma in Pain Research

Nociception

Pain

Suffering

Pain behaviors

Classical Approaches to Pain


Anatomical


Anatomical Physiological


Anatomical Physiological Pathological


Anatomical Physiological PathologicalPsychological

傷害性刺激: Nociception

Damage

Response

Transmission of Pain

Injury

Peri-aqueduct gray

PeripheralNerve

Dorsal RootGanglion

C-Fiber

A-beta FiberA-delta Fiber

Spinothalamic tract

Dorsal Horn

Brain

Spinal Cord

Somatosensory cortex

Ant cingular cortex

Nerve Distribution

The Dual Pathway

Pain stimulus

Dorsal horn

Sensorycortex

Dorsal rootganglia

Perception

Modulation

Transmission

Transduction NE

5-Ht

Opioid

Die in peace...

神蹟？催眠？

The scope of pain

分子

生物體

社會群體

分子運動

訊息傳遞

基因調節

神經系統

嬰幼期變化 c-Fos

AP-1

c-Jun-pp

AP-1 site

Dynorphin

c-Jun-ppp

p

CREB

Immediate early gene

Molecular marker of pain

ms sec min hour day week month year

AMPA

NMDA,Sub-P, CGRPCa, NO, PKC

apoptosis ???

Neuronal Sprouting

dynorphinNPY, galanin

c-fos

Kao & Sun, Chinese J Pain, 2003.

pErk

medialpathway

lateralpathway

Damage

Sensory discriminative

response

Emotional cognitive response

Somatosensorycortex

Ant cingularcortex

Current Dimensions of Pain

Sensory

Damage

Response


Sensory

EmotionalDamage

Response


CognitiveSensory

EmotionalDamage

Response


Sociobehavioral

CognitiveSensory

EmotionalDamage

Response

Pain-Sleep-Mood Cycle

Panic, GAD, OCD Depression,and acute anxiety all associated with sleep disruption

Sleep deprivation increases anxiety, stress

hormones and sympathetic tone

Sleep disturbance

Anxiety

Pain

疼痛的分期

急性疼痛慢性疼痛

Somatic

Visceral Neuropathic

疼痛的總類

Mixed TypeCaused by a

combination of both primary injury or

secondary effects

Clincal Pain Nociceptive

PainCaused by activity in neural pathways in

response to potentially tissue-damaging stimuli

Neuropathic Pain

Initiated or caused by primary lesion or

dysfunction in the nervous system

Postoperativepain

Cancer painOsteoporosis

ArthritisBack pain

Postherpeticneuralgia

Neuropathic spinal stenosis

Cancer pain

Myofascial pain

Central post-stroke pain

Phantom pain

Trigeminalneuralgia

Polyneuropathy (eg,diabetic, chemotherapy)

孫維仁

Neuropathic Pain

代謝

缺血

遺傳

壓迫

創傷

中毒

感染

免疫

Etiology SyndromeSymptoms

自發性

經由刺激誘導

神經性疼痛

normal

spontaneous firing from damaged axon

spontaneous firing from spinal neuron

Ectopic Focus

鄰近正常Aβ活化

C fiber 受損

正常Aβ神經

NGF

Nerve Sprouting

Allodynia and Aβ Sprouting

X

III/IVV

I/II AβAβ

C

Allodynia and Aβ Sprouting

X

III/IVV

I/II

nociceptive neuronsafferent inputmodulationvisceral

non-nociceptive neurons

AβAβ

C

孫維仁

臨床表現

燒灼痛

觸感痛

緊繃感尖銳感電擊感

持續

持續

持續持續陣發性

時間發作

自發性

誘發性

自發性誘發性

Acute Herpes ZosterA few days…..

Acute Herpes ZosterA week…..

Sub-acute Herpes ZosterA few weeks…..

Post-herpetic NeuralgiaA few months…..

孫維仁

Natural Course of Herpes Zoster

BurningTactile-allodyniaTightnessPin-prickingShooting

Acute ChronicSub-acute

Peripheral CentralPeripheral+CentralSensitization

孫維仁

Central Sensitization

Normal

孫維仁

Central Sensitization

Normal Sensitized

孫維仁

Definition

"Stimulus– threshold

– modality

"Response– pain

intensity

Hyperalgesia HypesthesiaAllodynia

Threshold vs ResponseP

ain

Inte

nsity

10

8

6

4

2

0

Stimulus Intensity

Hyperalgesia

InjuryAllodynia

Normal

Hyperpathia

孫維仁

Targeted Approach

Mechanisms

Signs and Symptoms

Treatment

對症下藥

對病下藥

Management of Neuropathic Pain

• PharmaceuticalsAntidepressantsAnticonvulsantsLocal anestheticsNSAID’s/COX 2’sOpioidsα-adrenergic agentsTopical agents

• Nerve blocks– Sympathetic– Somatic

• Interventional therapies– Spinal cord stimulation– Intrathecal opioids– Neuro-lesioning

• Complementary– Acupuncture– Biofeedback/hypnosis

• Psycho-social consulting

Pain Treatment Continuum

Least invasive

Most invasive

Psychological/physical approachesTopical medications

Oral medications*

*Consider referral if previous treatments are unsuccessful.

Injections*Interventional techniques*

Continuum not related to efficacy.

鴉片類止痛劑

mu-Agonist

Efficacious

dose-dependent

no ceiling

Reliable

Predictable

NSAID

當然評價

mu-opioid

藥理作用藥品 μ κ 效價管制

Agonist

Morphine ++ 1 I

Demerol ++ 1/8 II

Fentanyl ++ 100 II

Tramadol + + 1/10 III

Propoxyphene + 1/3 IV

Codeine + 1/12 III

Partial Agonist Buprenorphine + 60 III

Agonist AntagonistNalbuphine - + 1 III

Butorphanol - + 10 IV

Antagonist Naloxone -- --

Pharmacodynamic Profiles

Adjuvants

✓ 便秘

✓ 小便滯留✓ 暈眩✓ 噁心嘔吐✓ 皮癢✓ 呼吸抑制

Laxatives & stimulants(peripheral opioid Ant)Alfa-1 blockerRitalinNovamine/Haldol/RemeronNalbuphine/ ButophanolNalbuphine/ Butophanol

WHO止痛階梯

WHO止痛階梯

非嗎啡類止痛藥

Step I

WHO止痛階梯


Step I

弱效嗎啡類止痛藥

Step II

WHO止痛階梯


Step I


Step II

強效嗎啡類止痛藥 Step III

WHO止痛階梯


Step I


Step II

強效嗎啡類止痛藥 Step III

九成

治癒

率

孫維仁

TherapeuticTOXIC

「低量開始，緩慢加量」

Serum Level

鎮痛消炎劑

孫維仁

Analgesic Action of NSAID

孫維仁


Arachidonic acid

Prostaglandins

孫維仁


COX 1 COX 2

Arachidonic acid

Prostaglandins

孫維仁


COX 1 COX 2

peripheral central

nociceptor activation

neuronal sensitization

Arachidonic acid

Prostaglandins

孫維仁


COX 1 COX 2

peripheral central

nociceptor activation

neuronal sensitization

NSAID

Arachidonic acid

Prostaglandins

孫維仁

Inflammation or Pain

COX-2

Pros

tagl

andi

ns

COX-1

InflamedNormal NSAID COX-2 specificinhibitor

COX-1 COX-1

Inflammation, pain

COX-1

孫維仁

COX-2

NSAID on COX-1/2

COX-1

N-terminal

Carboxylicgroup

of NSAIDforms

“salt bridge”with

Arginineat 120

C-terminalcontainingactive sites

Arachidonic Acid

NSAID(flurbiprofen)phenyl group

binds tohydrophobic

channel

N-terminal

Carboxylicgroup

of NSAIDforms“salt

bridge”with

Arginineat 120


Arachidonic Acid

NSAID(flurbiprofen)phenyl group

binds tohydrophobic

channel

Kurumbail et al. Nature. 1996; 384: 644-648

孫維仁

Specific COX-2 Inhibitor - “Side Pocket”

Hydrophilic “side pocket”

N-terminal


Arg 513,Hist 90 – forms hydrogen bonds with oxygen in sulfonamide side chain

Specific COX-2 inhibitor – phenyl group binds tohydrophobic channel

Arachidonic Acid

Arg 120

Kurumbail et al. Nature 1996; 384: 644-648

抗憂鬱劑

Antidepressants in

Multiple mechanisms of action

RCTs and meta-analyses demonstrate benefit of

amitriptyline, nortriptyline, desipramine

Variable onset of analgesia

Independent of antidepressant activity

Improvements in insomnia, anxiety, depression

*Not approved by FDA for this use.

Tricyclic Antidepressantsfor Neuropathic Pain Disorders

Start at 10-25 mg at bedtimeincrease every few days as tolerated to a target dose of 50 mg

if no effect at 2 wk, continue to increase

may need ≥150 mg

Can split dose to reduce side effects

Expect partial effectuse multiple agents

Consider preprescription cardiac evaluation

Tricyclic Antidepressants: Adverse Effects (AEs)

• Commonly reported AEs (generally anticholinergic):– blurred vision– cognitive changes– constipation– dry mouth– orthostatic hypotension– sedation– sexual dysfunction– tachycardia– urinary retention

• Desipramine

• Nortriptyline

• Imipramine

• Doxepin

• Amitriptyline

FewestAEs

Most AEs

Pharmacodynamic profiles

Receptor 5-HT NE

clinical actions

antidepressionanxiolysis

antidepressionenhanced drive

side effectnausea,vomitingGI symptomsheadache

tachycardiatremorsympathomimetic

Clinical ManifestationReceptor 5-HT1 5-HT2 5-HT3

action antidepressionanxiolysis

side effect

insomniaagitationnervousnesssexual disorder

nauseavomitingGI symptomsheadache

Effect of mirtazapine on aminergic neurons

NA cell body

5-HT cell body

presynaptic NA neuron

α2-autoreceptor

presynaptic 5-HT neuron

postsynaptic 5-HT neurons

5-HT1 5-HT2 5-HT3

postsynaptic NA neuron

noradrenaline serotonin

α2-heteroreceptor

Remeron

vesicle

α2-autoreceptor

α1-adrenoreceptor

Remeron

Sleep improvement !via block 5-HT2 receptors

You need to know !

抗癲癇製劑

Gabapentin

α2δ GABA

Clinical ApplicationsNeuropathic Pain

Post-herpetic neuralgia

Diabetic painful neuropathy

Trigeminal neuralgia

Acute herpes zoster

Acute HIVD

Sleep disorder

介入性止痛術

Epidural Injection

Inter-laminar

Trans-foraminal

Headache

inflammatory pain

spasticity-induced pain

Botulinum and Analgesia

Migraine ++ Tension-type ??

疼痛病患問題的特質

痛覺感受的異常性

生理狀況的脆弱性

心理問題的複雜性

疾病進展的多樣性

藥物反應的不定性

Delimma of Pain Management

Analgesia Side effect

Pain Sufferings

Treatment

療效

副作用

止痛越強=副作用越強？

嗜血的殺手？

還是，混口飯吃？

The Strategy

Mechanisms

Signs and Symptoms

Treatment

對症下藥

對病下藥

慢性疼痛治療原則

Nociceptive-- somatic origin-- visceral origin

Non-nociceptive-- somatic origin -- visceral origin-- neuropathic origin

Opioids!!

Adjuvant! Nerve block!

From Signal to Cells

spinal cord


spinal cord

dorsal horn


spinal cord

dorsal horn

Sensory neuron


From Damage to Sufferings

Damage

Response


Damage

Response



Damage

Response


Sociobehavioral

CognitiveSensory

Emotional

疼痛機制 the mechanism of pain

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