Introduction to Pain
Ed Bilsky, Ph.D.Department of PharmacologyUniversity of New England
Phone: 602.2707
E-mail: [email protected]
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
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