Introduction to Pain

Ed Bilsky, Ph.D.Department of PharmacologyUniversity of New England

Phone: 602.2707

E-mail: ebilsky@une.edu

Clinical Cases• 63 year old white female presents to the emergency room with an acute

outbreak of shingles following a recent episode of flu. She reports someitching at the site of the rash (lower right side of her trunk) that hasprogressed into a burning/stabbing pain (7/10) over the past two days.

• A 23 year old African-American male presents to the ER claiming to be havingan acute sickle cell crisis. He is visible agitated and reports that his pain is a10/10 and wants an injection of 150 mg of Demerol (meperidine).

• A 38-year-old man (70 kg) suffered for 48 h from an acute pain in the lumbarregion that was not improved with common drugs available at home(acetaminophen 1000  mg3/day). The pain was paroxystic with no analgesicposition The patient reported a previous history of renal acute pain. Clinicalexamination showed a maximal pain to pressure of the right lumbar region, amicroscopic haematuria, no elevated temperature, and VAS or NS equal to 5(0=no pain, 10=maximal pain). The X-ray of the abdomen showed a small opaqueobject in the projection of the fourth right lumbar vertebra. Theultrasonographic exam showed a moderate dilatation of the right urinarytract. The diagnosis was a right acute renal colic.

• Pain is defined by the International Associationfor the Study of Pain (IASP) as “an unpleasantsensory and emotional experience associatedwith actual or potential tissue damage, ordescribed in terms of such damage”

• Physiological pain serves an important protectiveand reparative function

Introduction to Pain

AdC

Peripheral Nerve Fibers

C

Aα

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pain

Normal

Protective

Acute Prolonged

Reflexes Inflammationand Repair

Abnormal

Non-protective

Chronic(Pain as Disease)

Healing of injured tissue can occurbut pain continues

Therapeutic goal:return sensitivity to normal thresholdswithout loss of protective function (anti

hyperalgesia/anti-allodynia)

• In contrast to normal pain states, pathologicalchronic pain serves no apparent purpose

• Furthermore it poses significant health andsocial problems in the United States andelsewhere– quality of human life– economic costs

Impact of Chronic Pain

Incidence and Cost of Various Neurological Disorders

Disease Cases Cost Cost/Case

Chronic Pain 90 million $100 billion $1,100

Addiction 30 million $160 billion $5,333

Alzheimer’s 4 million $90 billion $22,500

Stroke 3 million $25 billion $8,333

Schizophrenia 2 million $32.5 billion $16,250

Parkinson’s 0.5 million $6 billion $12,000

Spinal Injury 0.3 million $10 billion $33,000

National Institutes of Health, 1998

• Transduction - Noxious stimuli are converted toelectrical signals in sensory nerve endings

• Transmission - neural events which relay theinformation from the periphery to the cortex

• Modulation - the nervous system can selectivelyinhibit the transmission of pain signals

• Perception - subjective interpretation by the cortexof the noxious stimulus.

• Sensory component

• Affective component

Processing of Pain Signals

Relay and DescendingModulation

Cortex

Thalamus

Central Perception

BrainStem

Spinal Cord

Peripheralstimulus

Transmission

Signal Transduction

“Top-down” ModulationDescending Modulation inChronic Pain States

Ascending Transmission - Novel Therapies

Pain is a Sensory Experience

- Emotion - Attention/Distraction - Expectation - Stress

• Pain Detection Threshold– a property of the sensory system– highly reproducible in individuals

• Pain Tolerance– Highly variable among individuals– dependent on affective components

The Variability of Pain

Neural Mechanisms of Pain Transduction and Transmission

PainPainAvoidanceAvoidanceEmotionalEmotionalreactionreaction

Dorsal RootGanglia

(cell body)

Spinal cord

WithdrawalWithdrawal

Transduction Conduction Transmission Perception

Transduction of Nociceptor Activators

TRPVsASICsTRPV1

TRPMsGPCRs

Tyrosin

e Kinas

es ASICsTRPV4TREK-1

Purinoce

ptors

Protons Mechanicalforce

HeatCapsaicinWasabi

Mustard oil

ColdHistamineATP

H+

G

Not all receptors arenecessarily co-localized onthe same cell membrane

Pain Transmission Fibers

Modality

(0.5 - 2 m/sec)

ThermalPressureChemical

Type C-PolymodalNociceptors

Conduction

AdNociceptors

(5 - 20 m/sec)

High-ThresholdMechanoreceptors

Pressure ThermalPressure

Spikes

HeatStimuli

4835

(oC)

Peripheral Nociceptors Do Not Adapt

• Sensitization of high-thresholdmechanothermal nociceptor

45oC

Nociceptor Stimulus Non-nociceptivethermoreceptor

Magnitude of afferentresponse

0

Temperature (oC)

Thermoreceptor

Nociceptor

40 45 50

Peripheral Nociceptors Do Not Adapt

Injury-Induces Changes in Pain Detection and Sensation

Stimulus intensity

Resp

onse

Hyperalgesia: an increased responseto a normally painful stimulus

Pain threshold

Pain threshold

Allodynia: a painful response to anormally innocuous stimulus

Stimulus intensity

Resp

onse

Nerve BlockNo secondaryhyperalgesia

Primary Hyperalgesia(Peripheral Sensitization)

Secondary Hyperalgesia(Central Sensitization)

Stimulus temperature (oC)49474541 43

1

2

3

4

5

6

Sub

ject

ive

Pain I

nten

sity

0

post-injury

Allodynia Hyperalgesia

pre-injury

Peripheral Nociceptor Sensitization and Neurogenic Inflammation

• Direct activation of nociceptor

• Sensitization of nociceptor

• Chemicals produced only duringtissue injury

Calor vasodilation --> heat

Rubor vasodilation --> redness

Tumor plasma extravasation -->swelling

Dolor activation of peripheraland adjacent nociceptors

Glucocorticoids

NSAIDS

Serotonin

Bradykinin

Histamine

Prostaglandins

Leukotrienes

Substance P

Platelets

Plasma Kininogen

Mast Cells

Damaged Cells

Damaged Cells

Primary Afferents

++

+++

+

-

-

-

Potassium Damaged Cells ++ Activate

Activate

Activate

Activate

Sensitize

Sensitize

Sensitize

Substance Source Pain in Man Effect on Primary

Afferents

Chemical Mediators in Nociceptive Transmission

Human Brain Imaging of Heat Pain

Somatosensory Cortex

AnteriorCingulate

Cortex

Insular Cortex

Somatosensory CortexAnterior Cingulate Cortex

InsularCortex

Thalamus

Spinomesen-cephalic Tract

Injury

PrimaryAfferent

Nociceptors

AnterolateralSystem

C

IIIIII

IVV

Prefrontal Cortex

Thalamus

SpinoreticularTract

0 2 4 6 8 10 12 14 160

5

10

15

20

25

Stimulus number

Spikes

per

stimulus

Persistent Nociceptive Input Changes Responses of2nd Order Cells in the Spinal Dorsal Horn

Windup Induced by Repetitive C-Fiber Stimulation

Mechanisms of Central Sensitization

Primary Afferent Neuron

NK-1 AMPANMDA

Second Order Neuron

Summation of slow synaptic potentialsNMDA and neurokinin mediated

Alteration in second messengers (Calcium, IP3, DAG etc)

Protein kinase activation -->Phosphorylation of receptors and ion channels

Increased excitabilityand synaptic efficacy

Central sensitization

Repetitive C-fiber input

Presynaptically:• Repetitive C-fiber input• Increased transmitter release

Postsynaptically:• Increased response to

transmitter• Strengthening of

“synaptic efficacy”

Gate Theory of Pain

Ab Low Threshold Mechanoreceptor

C/Ad Nociceptor

2nd Order PainTransmission CellTo Thalamus

InhibitoryInterneuron

(e.g., GABA?)

Transcutaneous Electrical NerveStimulation

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SpinalCord

ReticularFormation

MedialThalamus

LateralThalamus

AssociationCortex

Somato-sensoryCortex

Sensation

Affect

PaleospinothalamicNeospinothalamic

Spinothalamic Tracts

Endogenous Opioids Regulate Nociception

SpinothalamicProjection to

Thalamus

IncreasedEnkephalin Release

Activation of Opioid Receptors:

• Decrease Ca++ Conductance

• increase K+ efflux

NociceptiveInput

ENK

Normal release ofglutamate, substance P

etc. promotes thetransmission of pain

DecreasedNeurotransmission

Supraspinal Analgesia• Brainstem circuits may inhibit

rostral movement ofnociceptive information andactivate descending pathwaysthat alter nociceptiveprocessing in the spinal cord– periaqueductal gray– rostral ventral medulla

• Parts of the limbic systemactivated by opioids may alterthe emotional response topainful stimuli– nucleus accumbens/ventral

forebrain

Amygdala

PainTransmission

Neuron

Descending Modulation → PAG indirectlycontrols pain transmission in the dorsal horn

PainFacilitationPain Inhibition

ACC

TH

PAG

DLPT

RVM

DorsalHorn

Modulation of Pain: Serotonin and Norepinephrine

Fields H. Nature Rev Neurosci 2004; 5:565-575.

RVM5-HT

Dorsalhorn

DLPTNE

Aß Fiber

Aß Fiber

C Fiber

5-HT

NE

III

III

IV

V

• DLPT: Dorsolateral Pontine Tegmentum (NE)• RVM: Rostroventral Medulla (5-HT)

Visceral Pain

Anatomical

Functional

mechanoreceptors

chemoreceptors

nociceptors?

thermoreceptors

polymodal

mucosa

muscle

Serosa/mesentery

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Visceral Pain

motor

sensory

noxiousstimulus

pain

spinal cord

Reflex Somatic Theory

• Pain occurs in the absence of a detectable ongoingtissue-damaging process;

• Abnormal or unfamiliar unpleasant sensations(dysesthesiae), frequently having a burning and/orelectrical quality;

• Delay in onset after precipitating injury;

• Pain is felt in a region of sensory deficit;

• Shooting or stabbing component;

• Normally non-noxious stimuli are painful (allodynia);

• Pronounced summation and after-reaction to noxiousstimuli (hyperalgesia).

Clinical Features of Neuropathic Pain

Radiation Therapy Injuryof Brachial Plexus

AbnormalPain

RadiationBurn

Normal

AvulsionRhizotomy

PeripheralLesion

Nerve Injury Induced Pain

Peripheral InjuryPeripheral Injury

UpregulateUpregulateGrowth-associatedGrowth-associated

ProteinsProteins

Cell Death &Cell Death &TransganglionicTransganglionicDegenerationDegeneration

RegenerativeRegenerativeCapacityCapacity

VacantVacantSynapsesSynapses

Formation Of NovelFormation Of NovelInappropriateInappropriate

SynapsesSynapses

Reorganization Of Spinal CircuitsReorganization Of Spinal Circuits

Injury Induced Changes in the Spinal Cord

Antihyperalgesic and/or Antiallodynic Agents Do NotNecessarily Produce Analgesia

NormalSensory Threshold

Hyperalgesia/Allodynia

AnalgesicAgents

Abnormal Sensory Threshold

Antihyperalgesic/Antiallodynic Agents

Physiological and Pathological Pain

Symptoms

Causes

Examples

Deafferentation

Burning, shooting, stabbing,paroxysms, vicelike, electric shockInjury to peripheral and/or CNS,from tumor infiltration or cancertherapy

Metastatic or radiation-inducedbrachial or lumbosacral plexopathies;spinal cord compression, postherpeticneuralgia

Neuropathic Cancer Pain

• Patients with pain:– at least 50% of all cancer patients– more than 70% of patients with advanced cancer

• Pain intensity:– moderate to severe in approximately 50% of

patients with pain– excrutiating in 30% of patients with pain

(Bonice, 1985; WHO, 1986)

50% TO 80% OF CANCER PATIENTS DO NOT OBTAIN

SATISFACTORY PAIN RELIEF

Scope of the Problem

Pain Management Techniques

Pharmacotherapy Non-Pharmacological Treatments

Physical therapy Procedures

Opioids Acupuncture Active exercise Trigger point injections

Nonsteroidals Relaxation Passive exercises Nerve blocks

Muscle relaxants Visualization Pool therapy Epidural steroids

Benzodiazepines Prayer TENS unit Intrathecal opioids

Antidepressants Pain groups Massage therapy Spinal cord stimulation

Antianxiety agents Chiropractic

Antiarrhythmics Ice/heat

Antiseizure agents Bed rest

• Pain is a highly variable sensation that has bothsensory and affective components– Great individual variability

• There is a key difference between statisticalsignificance and clinical significance when it comes toanalgesia

• A reduction in pain levels should not be equated tosufficient pain relief– Some patients may not be seeking complete pain relief; side-

effects may limit the maximum tolerated dose

Pain Assessment

• Assessment of pain in humans is unique in that patientscan typically verbalize both the intensity and quality ofthe pain, and how it is impacting their quality of life

• There are a number of inventories that have been usedto evaluate pain in humans

– Single-dimension self-report measures

– McGill Pain Questionnaire (MPQ)

– Brief Pain Inventory (BPI)

– West-Haven-Yale Multidimensional Pain Inventory (WHYMPI)

Pain Assessment

Visual Analog Scales– Used as self-report scales of

pain intensity

– Simple and efficient toadminister

– Effective for several patientpopulations because scaling isnot limited to words

www.ama.com

Rate Pain Intensity

McGill Pain Questionnaire

www.pain-education.com

– Used to quantify a patient’spain experience

– Consists of a series of 102pain descriptors that aregrouped into threedimensions of pain: sensory,affective, and evaluative

– Takes about 5 minutes tocomplete

Talk to Patients About Their Pain

• Talk to your Patients about their Pain

– Where is the pain located?

– What does it feel like (sharp, dull, burning)?

– When did it begin? How long does it last?

– What makes it better? What makes it worse?

• Rate Pain Intensity

– What is your level of pain most of the time? (0-10 scale)?

– When is your pain the worst/best?

– What is your pain level when your rest? During movement?

• Evaluate Limitations on Activities

– What daily activities do you avoid because of pain?

– Does pain interfere with your ability to sleep/walk/work/play?

– How does pain affect your mood and relationships?

American Pain Foundation

Pain Assessment Questions to Ask

Fully active without restriction 0

Activity restricted; ambulatory;“light” work only 1

Ambulatory; all self-care;no work activities;

up > 50% waking hours

Limited self-care;Confined > 50%Waking hours

2

3

4Completelydisabled

www.painfoundation.org

Evaluate Limitations on Activities

• Pain is often associated with other emotions that canexacerbate the situation– Anxiety, loss of control, etc.

• Interventions should be initiated that minimize theseemotions– Involving the patient in the overall plan (e.g., PCA)– Nonpharmacological strategies including reassurance, distraction, etc.– Use of adjunct agents including anxiolytics, antidepressants, etc.

Affective Aspects of Pain Management

• Use nonpharmacological treatments to reduce pain– Distraction, hypnosis, etc.– Encouraging the patient to use techniques that have

worked for them

• Use of nitrous oxide or fentanyl for settingfractures– No need for the “this will only hurt for a minute”

• Regional anesthesia in elderly patients toeliminate the cognitive effects of opioids andother CNS acting agents

Additional Analgesia Options

1. Analgesia should be integrated into a comprehensive patient evaluationand management plan

2. The emotional and cognitive aspects of pain must be recognized andtreated

3. There is no reliable way to objectively measure pain

4. Pain is most often under-treated, not over-treated

5. Beware of the “squeaky-wheel-gets-the-oil” phenomenon of pain control

6. Pain control must be individualized

7. Anticipate rather than react to pain

8. Whenever possible, let the patient control his or her own pain

9. Pain control is often best achieved by combination therapy

10. Pain control requires a multidisciplinary team approach

Principles of Pain Control