OPIATESPsych 181: Dr. AnagnostarasLecture 8

OpioidsOpioids

OpiatesOpiates alkaloids found in the opium poppy alkaloids found in the opium poppy

(Papaver somniferum)(Papaver somniferum) [Gk. opion = “poppy juice”][Gk. opion = “poppy juice”]

OpioidsOpioids compounds with opiate-like actions, compounds with opiate-like actions,

including, but not confined to opiates (e.g., including, but not confined to opiates (e.g., synthetic, endogenous opioids)synthetic, endogenous opioids)

Types of opioidsTypes of opioids

1. Naturally-1. Naturally-occurringoccurring opium opium sap fromsap from

opium poppyopium poppy

Two major activeTwo major activealkaloidsalkaloids morphinemorphine codeinecodeine

MorphineMorphineMorphineMorphine

Morpheus (god of Dreams)Morpheus (god of Dreams)

-son of Hypnos-son of Hypnos ~ 10% of opium~ 10% of opium

by weightby weight

HO O OH

N CH3

H

Morphine

CodeineCodeine

methylmorphinemethylmorphine ~ 0.5% of~ 0.5% of

opiumopium

2. Semi-synthetics2. Semi-synthetics

2. Semi-synthetics2. Semi-synthetics

HeroinHeroin diacetylmorphinediacetylmorphine addition of two acetyl groups to morphineaddition of two acetyl groups to morphine ~ 10x more potent than morphine~ 10x more potent than morphine pharmacological effect usually thought to pharmacological effect usually thought to

be identical to morphinebe identical to morphine in brain: heroin > morphinein brain: heroin > morphine

(new data suggest morphine and heroin(new data suggest morphine and heroinmay have different actions; 1999)may have different actions; 1999)

Semi-synthetic analgesicsSemi-synthetic analgesics

Hydromorphone (Dilaudid®)Hydromorphone (Dilaudid®) Hydrocodone (Hycodan®, Vicodin®)Hydrocodone (Hycodan®, Vicodin®) Oxycodone (Percodan®, Oxycontin®)Oxycodone (Percodan®, Oxycontin®)

3. Synthetics3. Synthetics

PhenylpiperidinesPhenylpiperidines Fentanyl “china white”Fentanyl “china white” Carfentanil (Wildnil®)Carfentanil (Wildnil®) Meperidine (Demerol®)Meperidine (Demerol®)

(MPPP)(MPPP)

Methadone & CongenersMethadone & Congeners Methadone (Dolophine®)Methadone (Dolophine®) Propoxyphene (Darvon®)Propoxyphene (Darvon®)

Benzomorphans Benzomorphans Pentazocine (Talwin®)Pentazocine (Talwin®)

N CH3

CH2C O

O

CH3

Pethidine (Meperidine)

NH

(CH3)2

Methadone

CH2C

O

CH3

H3C

Analgesic potencyAnalgesic potency

Analgesic potency

Mild to moderate pain

Moderately severe pain

Severe pain

codeine, propoxyphene (Darvon®)

meperdine (Demerol®)

heroin, hydromorphone (Dilaudid®)

"Perc-a-pop"

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

4. Opioid antagonists4. Opioid antagonists

naloxone (Narcan®)naloxone (Narcan®) naltrexonenaltrexone

Suboxone® (buprenorphine + naloxone)Suboxone® (buprenorphine + naloxone)

5. Endogenous opioids5. Endogenous opioids

Enkephalins, endorphins and dynorphinsEnkephalins, endorphins and dynorphins Morphine & codeine?Morphine & codeine?

History of use - opiumHistory of use - opium

Since recorded historySince recorded historyIngredient in allIngredient in all

sorts of medicinalsorts of medicinal

preparationspreparations

History of use - morphineHistory of use - morphine

“Soldiers disease”

History of useHistory of use

Ads for heroinAds for heroin

Major effectsMajor effects

AnalgesiaAnalgesia Relief of pain in absence of impairment in Relief of pain in absence of impairment in

other sensory modalitiesother sensory modalities

Euphoria - PleasureEuphoria - Pleasure Produce sense of well being, reduce Produce sense of well being, reduce

anxiety, positive feelingsanxiety, positive feelings

Other effectsOther effects

Nausea & vomitingNausea & vomiting Respiratory depressionRespiratory depression Miosis (opposite of mydriasis)Miosis (opposite of mydriasis) Gastrointestinal effectsGastrointestinal effects Cough SuppressionCough Suppression Motor effectsMotor effects

Effects of repeated administrationEffects of repeated administration

Tolerance, withdrawal & sensitization

Tolerance and withdrawalTolerance and withdrawal

20

10

01 4 6 24 72 64 24 721

8

6

4

2

0

Naltrexone Morphine Control

Time (hr)Beh

avio

ral

wit

hd

raw

al s

core

LC

un

it a

ctiv

ity

12.18

SensitizationSensitization

Psychomotor stimulant effectsPsychomotor stimulant effects Rewarding effectsRewarding effects

(conditioned place preference)(conditioned place preference)

Mechanisms of actionMechanisms of action

Primary action on opioid receptors located in Primary action on opioid receptors located in CNS +/or peripheryCNS +/or periphery

Different effects due to action atDifferent effects due to action at Different receptor subtypesDifferent receptor subtypes Receptors in different locationsReceptors in different locations

Endogenous opioidsEndogenous opioids

Production ofClassical transmitter Peptide transmitter

(1) Synthesizing enzymes(2) Storage vesicles

Axonal transport of(1) Synthesizing enzymes(2) Storage vesicles

Axonal transport of(1) Storage vesicles

Supply by(1) Axonal transport + storage(2) New synthesis(3) Reuptake

Release Release

Supply by(1) Axonal transport + storage

Production of(1) Peptide (precursor)

(3) Converting enzymes

(2) Storage vesicles

11.4

Post-translational processing

Translation

Opioid peptide gene familiesOpioid peptide gene families

Three different gene familiesThree different gene families Proopiomelanocortin (POMC)Proopiomelanocortin (POMC) ProenkephalinProenkephalin Prodynorphin (‘proenkephalin B’)Prodynorphin (‘proenkephalin B’)

Proopiomelanocortin

Proenkephalin

Prodynorphin

Signal NH2

Signal NH2

Signal NH2

g-MSH

α-MSH β-LPHCLIP

β-MSH β-EndorphinACTHCOOH

( 6– 7– 8)Arg Gly Leu

5 6 71 2 3 4COOH

α-Neoendorphin

Dyn A Dyn Bβ-Neoendorphin

COOH

-Met enk( 6– 7)Arg Phe

-Met enk

12.5

Precursor gene families Precursor gene families

Proopiomelanocortin (POMC)Proopiomelanocortin (POMC) ß-endorphinß-endorphin ACTH, melanocortin SHACTH, melanocortin SH

Proenkephalin -> Enkephalins Proenkephalin -> Enkephalins met-enkephalin & 2 extended met-enkmet-enkephalin & 2 extended met-enk leu-enkephalinleu-enkephalin

Prodynorphine - forms of leu-enkephalin Prodynorphine - forms of leu-enkephalin Dynorphins, A and BDynorphins, A and B Neoendorphins, µ and Neoendorphins, µ and ββ

Differential distributionDifferential distribution

EndorphinsEndorphins discretediscrete hypothalamic - endocrine relatedhypothalamic - endocrine related

Enkephalins and DynorphinsEnkephalins and Dynorphins wide distribution, local circuit and short wide distribution, local circuit and short

axon projectionsaxon projections

Opioid receptorsOpioid receptors

Opioid receptorsOpioid receptors

SubtypeSubtype Preferred LigandPreferred LigandMu (µ)Mu (µ) Morphine & endorphinsMorphine & endorphins

Delta (Delta ()) EnkephalinsEnkephalins

Kappa (Kappa ()) Ketocyclazocine & dynorphinsKetocyclazocine & dynorphins

Each subtype has subtypesEach subtype has subtypes

Opioid receptorsOpioid receptors

Cellular actionsCellular actions

G protein coupled receptorsG protein coupled receptors inhibitoryinhibitory

Adenylyl cyclase

ATPcAMP

Protein kinase A

β βαα

GsGi

γ γ

Opioid receptor

12.4

Negatively-coupled

Role in drug actionRole in drug action

AnalgesiaAnalgesiaAnalgesiaAnalgesia

Dorsal horn

Ventral horn

Dorsal root (sensory)

Ventral root (motor)

4.2

Spinal actionsSpinal actions Dorsal horn Dorsal horn

of spinal cordof spinal cord primary pain primary pain

afferentsafferents

Sensory neuron

Projection neuron

Spinalcord+

AnalgesiaAnalgesiaAnalgesiaAnalgesia

Spinal actionsSpinal actions inhibit incoming pain signalsinhibit incoming pain signals

Opioid receptor

12.8

AnalgesiaAnalgesiaAnalgesiaAnalgesia

Supraspinal actionsSupraspinal actions

12.10

Diencephalon

Brain area Descending pathways

Midbrain

Rostroventralmedial medulla (RVM)

Spinal cord

NR NP

DLPT LC

PAG

Dorsal horn

PVG

AnalgesiaAnalgesiaAnalgesiaAnalgesia

Supraspinal actionsSupraspinal actions

12.10

Diencephalon

Brain area Descending pathways

Midbrain

Rostroventralmedial medulla (RVM)

Spinal cord

NR NP

DLPT LC

PAG

Dorsal horn

PVG Stimulation >analgesia andinhibit cells in dorsal horn

AnalgesiaAnalgesiaAnalgesiaAnalgesia

Supraspinal actionsSupraspinal actions

12.10

Diencephalon

Brain area Descending pathways

Midbrain

Rostroventralmedial medulla (RVM)

Spinal cord

NR NP

DLPT LC

PAG

Dorsal horn

PVG Lesion > block analgesiato systemic or local morphine

AnalgesiaAnalgesiaAnalgesiaAnalgesia

Supraspinal actionsSupraspinal actions µ1 sites seem most importantµ1 sites seem most important Specific blockade of µ1 shifts dose-Specific blockade of µ1 shifts dose-

response curve for morphine analgesia up response curve for morphine analgesia up to 12 fold to rightto 12 fold to right

AnalgesiaAnalgesiaAnalgesiaAnalgesia

Heroin vs. MorphineHeroin vs. Morphine

difference pharmacokinetic?difference pharmacokinetic?

recent evidence for different receptorsrecent evidence for different receptors

- MOR-1 knockouts- MOR-1 knockouts

Analgesia - Analgesia - MOR1 knockoutsMOR1 knockoutsAnalgesia - Analgesia - MOR1 knockoutsMOR1 knockouts

An

alg

esia

(%

)

Schuller et al., Nature Neurosci. (1999)

heroin > 6-acetyl-morphine in vivo

Morphine, but not heroin, analgesiaabolished in Mor1 knockout mice

Reinforcing effectsReinforcing effects

Reinforcing effectsReinforcing effects

All classical opioid drugs of abuse have a All classical opioid drugs of abuse have a preference for µ sites (e.g., morphine, heroin, preference for µ sites (e.g., morphine, heroin, methadone, fentanyl etc.)methadone, fentanyl etc.) may contribute, but little knownmay contribute, but little known

compounds are not self-administeredcompounds are not self-administered psychomimetic and aversive in humanspsychomimetic and aversive in humans

Opioid/DA interactionOpioid/DA interaction

Intra-VTA opioid support SA and CPPIntra-VTA opioid support SA and CPP DA antagonist or 6-OHDA lesion impair SADA antagonist or 6-OHDA lesion impair SA DA antagonist into VTA or ACC impair SADA antagonist into VTA or ACC impair SA

MechanismMechanismMechanismMechanism

µ compounds:µ compounds: Increase DA cell firingIncrease DA cell firing Increase DA release in ACCIncrease DA release in ACC Accompanied by locomotor activationAccompanied by locomotor activation

Model for reinforcing effectsModel for reinforcing effects

Site of actionSite of action VTA – accumbens DA systemVTA – accumbens DA system

DA

β-endorphin

GABA

Ventraltegmental

( )area VTA

Nucleusaccumbens

Ventral pallidum

Mesolimbic dopamine

––

12.16

“Disinhibition”

compounds compounds

Decrease DA cell firingDecrease DA cell firing Decrease DA releaseDecrease DA release Decrease locomotionDecrease locomotion

Respiratory depressionRespiratory depression

µ2 sites?µ2 sites? Specific µ1 antagonist (naloxonazine) shifts Specific µ1 antagonist (naloxonazine) shifts

analgesia dose - response curve for morphine analgesia dose - response curve for morphine to rightto right

Not shift dose-response curve for:Not shift dose-response curve for: elevation of pCo2elevation of pCo2 depression of pO2depression of pO2

Respiratory neurons in medulla in region of n. Respiratory neurons in medulla in region of n. solitary tractsolitary tract

Gastrointestinal effectsGastrointestinal effects

µµ and and sites In stomach, small and large intestineIn stomach, small and large intestine Decreased motilityDecreased motility Common bioassay > ability to inhibit Common bioassay > ability to inhibit

intestinal contractionsintestinal contractions

MOR KnockoutsMOR Knockouts

Morphine has affinity for all opioid receptor Morphine has affinity for all opioid receptor subtypes (much stronger for mu)subtypes (much stronger for mu)

Evidence for site of action from Evidence for site of action from pharmacological experiments with drugs that pharmacological experiments with drugs that may act at multiple sitesmay act at multiple sites

Which effects due to action at which receptpr Which effects due to action at which receptpr subtypes?subtypes?

MOR Knockouts (MOR -/-)MOR Knockouts (MOR -/-)

Morphine effectMorphine effect

Spinal analgesiaSpinal analgesia AbolishedAbolished

Supraspinal analgesiaSupraspinal analgesia AbolishedAbolished

RewardReward AbolishedAbolished

WithdrawalWithdrawal AbolishedAbolished

Respiratory depressionRespiratory depression AbolishedAbolished

Inhibition GI motilityInhibition GI motility AbolishedAbolished

Psychoactivating effectPsychoactivating effect AbolishedAbolished

(all effects maintained in DOR-/- and KOR-/-)(all effects maintained in DOR-/- and KOR-/-)

Brigitte L. Kieffer, Opioids: first lessons from knockout mice, Brigitte L. Kieffer, Opioids: first lessons from knockout mice,

Trends in Pharmacological SciencesTrends in Pharmacological Sciences, 20 (1999) 19-26., 20 (1999) 19-26.

The Politics of PainThe Politics of Painand Pain Managementand Pain Management

IntroductionIntroduction

PrevalencePrevalence Pain accounts for 80% of all medical Pain accounts for 80% of all medical

complaints (30% debilitated at some time)complaints (30% debilitated at some time) Pain is patient's #1 reason why they fear Pain is patient's #1 reason why they fear

diseasedisease Pain affects 90% of patients with terminal Pain affects 90% of patients with terminal

disease (50% of ambulatory patients)disease (50% of ambulatory patients) Obstacles for treatmentObstacles for treatment

Fear—patient, prescriberFear—patient, prescriberSocial and Legal obstaclesSocial and Legal obstacles

Lack of educationLack of education

Political and Social ObstaclesPolitical and Social Obstacles

• • Overstated abuse potential of opiate drugs Overstated abuse potential of opiate drugs has been a serious obstacle to pain has been a serious obstacle to pain treatmenttreatment

• • Pain patients have been a casualty of the Pain patients have been a casualty of the war on drugswar on drugs

• • No field to study pain until the 1970sNo field to study pain until the 1970s

(opiate receptor cloned)(opiate receptor cloned)

• • Very little formal training on pain Very little formal training on pain management as part of medical school management as part of medical school curriculum (often 1 hour)curriculum (often 1 hour)

Politics of painPolitics of pain

• • Most doctors misinformed about the Most doctors misinformed about the addictiveness of therapeutic opiates (e.g., addictiveness of therapeutic opiates (e.g., vicodin v heroin or significance of routes vicodin v heroin or significance of routes of administration in addiction)of administration in addiction)

• • Even when habit-forming this addiction Even when habit-forming this addiction outweighed thinking about patient's outweighed thinking about patient's quality of life.quality of life.

• • Fear of reprisals on license by DEA a major Fear of reprisals on license by DEA a major issueissue

• • Drug companies avoided new opiatesDrug companies avoided new opiates

Politics of painPolitics of pain

• • Pain patients looked down upon for Pain patients looked down upon for complaining about pain (especially chronic complaining about pain (especially chronic pain)pain)

• • Pain treated as a valuable diagnostic indicator Pain treated as a valuable diagnostic indicator by doctors "don't want to cover up the pain" by doctors "don't want to cover up the pain" (even chronic neuropathic pain)(even chronic neuropathic pain)

Politics of painPolitics of pain

• • Revolution in pain management had multifaceted Revolution in pain management had multifaceted roots- began in 1970sroots- began in 1970s

• • conference on Pain formed unified field to conference on Pain formed unified field to study Pain, 1977 - American Pain Society (study Pain, 1977 - American Pain Society (www.ampainsoc.orgwww.ampainsoc.org) 28-3600) 28-3600

• • discovery of endogenous opioidsdiscovery of endogenous opioids

• • activism by Bonica, Liebeskind, etc.activism by Bonica, Liebeskind, etc.

• • revolt by San Francisco cancer doctorsrevolt by San Francisco cancer doctors

• • Centers for Pain Management Policy (e.g., Centers for Pain Management Policy (e.g., Wisconsin)Wisconsin)

Politics of painPolitics of pain

• • Several states enacted legislation to protect Several states enacted legislation to protect doctors and patients (e.g., California's "pain doctors and patients (e.g., California's "pain patients bill of rights")patients bill of rights")

• • Softening of war on drugs by Clinton Softening of war on drugs by Clinton administrationadministration

• • Doctor's take back their rightsDoctor's take back their rights

(Doctor's make medical decisions)(Doctor's make medical decisions)

• • Medical marijuana actsMedical marijuana acts

Politics of painPolitics of pain

• • In cancer was clear need to treat pain In cancer was clear need to treat pain outweighed any addictionoutweighed any addiction

• • It became clear most pain patients either It became clear most pain patients either didn't become addicted at all or developed didn't become addicted at all or developed mild dependencemild dependence

• • Pain management clinics have appeared all Pain management clinics have appeared all over the place (including Emory)over the place (including Emory)

• • Still many obstacles to adequate pain Still many obstacles to adequate pain management, e.g., patient access is still very management, e.g., patient access is still very low and too many drug side-effectslow and too many drug side-effects

Many obstacles remainMany obstacles remain

• • Still difficult for patients to get treatmentStill difficult for patients to get treatment

• • triplicate prescriptionstriplicate prescriptions

• • cannot be called in cannot be called in

• • cannot be refilledcannot be refilled

• • policing by DEApolicing by DEA

• • few experts in painfew experts in pain

• • strong slow-release drugs are expensivestrong slow-release drugs are expensive

• • pain patients often poor, uninsured, and pain patients often poor, uninsured, and cannot travel or workcannot travel or work

What is Pain?

Medical DefinitionMedical Definition

““Pain is an unpleasant sensory and emotional Pain is an unpleasant sensory and emotional experience associated with actual or potential experience associated with actual or potential tissue damage or described in terms of such tissue damage or described in terms of such damage”damage”

International Association for the Study of Pain, International Association for the Study of Pain, 19791979

Operative DefinitionOperative Definition

““Pain is whatever the experiencing person says it Pain is whatever the experiencing person says it is, existing whenever he/she says it does.”is, existing whenever he/she says it does.”

••patient's appearance can be very deceptivepatient's appearance can be very deceptive

What is Pain?

Current definitions of pain don't work well Current definitions of pain don't work well for:for:

• • children who can't speak or even older children who can't speak or even older ones who can't express themselves wellones who can't express themselves well

• • those who are mute or mentally illthose who are mute or mentally ill

• • animalsanimals

• • those who hide their painthose who hide their pain

•• •• emphasis on pain behaviors emergingemphasis on pain behaviors emerging

Reflection tells me that I am so far from being able to define pain, of which I here write, that the attempt could serve no useful purpose. Pain, like similar subjective things, is known to us by experience and described by illustration.

Pain is a perception, nociception is the sensation

Thomas Lewis. Pain. New York, The MacMillan Company, 1942.

NOCICEPTION

PAIN

SUFFERING

PAIN BEHAVIOR

DefinitionsDefinitions

Nociception: Potentially tissue damaging thermal, mechanical or chemical energy impinging upon specialized nerve endings of A- and C fibers.

Pain: Perceived nociceptive input to the nervous system.

Pain can occur without nociception!

Pain syndromes without nociceptionPain syndromes without nociception

Thalamic syndrome Phantom limb pain

Tic douloureux Arachnoiditis

Postherpetic neuralgia Atypical facial pain

Postparaplegia pain Nerve root avulsion pain

Postthoracotomy pain Neuropathic pain

Pain is a major cause of suffering!Pain is a major cause of suffering!

Suffering: Negative affective response generated in higher nervous system regions in response to pain and other situations including fear, anxiety, isolation, depression, etc.

Pain behaviorPain behavior

All forms of behavior generated by the individual that are commonly understood to reflect the presence of nociception; for example, grimacing, saying ouch, limping, lying down, taking medicines, seeking health care, refusal to work.

Types of PainTypes of Pain

Nociceptive PainNociceptive Pain Stimulation of somatic and visceral Stimulation of somatic and visceral

peripheral nociceptors by stimuli that peripheral nociceptors by stimuli that damage tissuedamage tissue

Neuropathic PainNeuropathic Pain Pain resulting from non-inflammatory Pain resulting from non-inflammatory

dysfunction of the peripheral/central dysfunction of the peripheral/central nervous system in the absence of nervous system in the absence of stimulistimuli

Neuropathic PainNeuropathic Pain

PrevalencePrevalence

General population 0.6-1%General population 0.6-1% CausesCauses

Compression/infilitration of nerves by:Compression/infilitration of nerves by: TumorsTumors Nerve Trauma secondary to proceduresNerve Trauma secondary to procedures Nervous System InjuryNervous System Injury E.g., phantom-limb pain, neuralgiaE.g., phantom-limb pain, neuralgia

back injury, post-surgical painback injury, post-surgical pain

Types of PainTypes of Pain

Transient PainTransient Pain• • Studied extensively in man and animalsStudied extensively in man and animals Does not involve tissue damageDoes not involve tissue damage

Activation of nociceptors in resting stateActivation of nociceptors in resting state

Not clinically relevant, save for procedural Not clinically relevant, save for procedural pain such as venipuncture, LPpain such as venipuncture, LP

Types of PainTypes of Pain

Acute PainAcute Pain Activation of nociceptors in region of Activation of nociceptors in region of

tissue damagetissue damage Nociceptor function is altered by tissue Nociceptor function is altered by tissue

changeschanges Healing processes can eliminate tissue Healing processes can eliminate tissue

damage; nociceptor function returns to damage; nociceptor function returns to baselinebaseline

Types of PainTypes of Pain

Chronic PainChronic Pain Activation of nociceptors in region of tissue Activation of nociceptors in region of tissue

damagedamage Nociceptor function is altered by tissue Nociceptor function is altered by tissue

damage; CNS adapts permanentlydamage; CNS adapts permanently Body cannot heal injury, or damage to Body cannot heal injury, or damage to

nervous system nervous system Organic cause unknown and untreatable Organic cause unknown and untreatable

(often iatrogenic)(often iatrogenic)

Chronic pain is a special problemChronic pain is a special problem

Chronic PainChronic Pain Associated with a social stigmaAssociated with a social stigma

people expect you to get over illnesspeople expect you to get over illness "get back to work""get back to work" associated with a lot of hiding of painassociated with a lot of hiding of pain

Debilitating and depressing producing lots of Debilitating and depressing producing lots of psychological problemspsychological problems

• • Especially poorly treatedEspecially poorly treated

• • lack of expertise and desire to treat by docslack of expertise and desire to treat by docs

• • lack of effective treatmentlack of effective treatment

Afferent pain transmission

Afferent fibers go to the CNS transmitting Afferent fibers go to the CNS transmitting nociceptive message from trauma to nociceptive message from trauma to dorsal horn of spinal corddorsal horn of spinal cord

A alpha, A beta, A gamma, A delta, B, or CA alpha, A beta, A gamma, A delta, B, or C Nociceptive transmission takes place in Nociceptive transmission takes place in

the A delta fibers (well-localized pain); C the A delta fibers (well-localized pain); C fibers (persistent pain)fibers (persistent pain)

Transduction of nociception

Conversion of stimuli into electrical action Conversion of stimuli into electrical action potentialpotential

What types of stimuli?What types of stimuli? Heat or cold (e.g. radiation damage)Heat or cold (e.g. radiation damage)

Pressure (e.g. tumor infiltration into Pressure (e.g. tumor infiltration into bone)bone)

Chemical (e.g. chemotherapy)Chemical (e.g. chemotherapy)

Peripheral Nociceptors

What is a nociceptor?What is a nociceptor?

Not spontaneously activeNot spontaneously active Level of stimulation must exceed thresholdLevel of stimulation must exceed threshold Sensitization produces hyperalgesiaSensitization produces hyperalgesia Tissue damage changes the sensitivityTissue damage changes the sensitivity

Sensitization is manifested as:Sensitization is manifested as:

Decreased thresholdDecreased threshold Increased intensity-prolonged firingIncreased intensity-prolonged firing Spontaneous activitySpontaneous activity

Pain Theories and Pathways

Spinal cord transmission–spinothalamic Spinal cord transmission–spinothalamic tract carries pain impulses; the lateral tract carries pain impulses; the lateral pathway (sharp, localized pain), the vental pathway (sharp, localized pain), the vental pathway (dull, nonlocalized pain)pathway (dull, nonlocalized pain)

Pathways merge in thalamus and connect in Pathways merge in thalamus and connect in cortexcortex

Ant Cingulate cortex–pain perception areaAnt Cingulate cortex–pain perception area

Types of Peripheral Nerve Fibers

AA FibersFibers (Fast Transmission) (Fast Transmission) Alpha - Proprioception (Muscles & Joints)Alpha - Proprioception (Muscles & Joints) Beta - Mechanoreception (Cutaneous Beta - Mechanoreception (Cutaneous

Tissue)Tissue) Delta - Primary nociceptive neuronsDelta - Primary nociceptive neurons

CC FibersFibers (Slow Transmission) (Slow Transmission) Primary nociceptive neuronsPrimary nociceptive neurons

Neuronal Activities in Normal States

Stimulus Pri Afferent Sensation

Low Intensity A-Beta Innocuous

High Intensity A-Delta/C Pain(nociception)

Neuronal Activities in Pain States

Stimulus Pri Afferent Sensation

Low Intensity A-Beta Pain (allodynia)

High Intensity A-Delta/C Hyperalgesia

Pain Theories and Pathways

Clusters of opiate receptors throughout Clusters of opiate receptors throughout ascending and ascending and descendingdescending pain pathways pain pathways

endogenous opioids also in brainendogenous opioids also in brain

Opiate receptors--µ (µ1 and µ2), Opiate receptors--µ (µ1 and µ2), (delta), (delta),

(kappa), ((kappa), ( sigma and sigma and epsilon)epsilon)

•• µ1 are primarily responsible for analgesic µ1 are primarily responsible for analgesic effects (but maybe also effects (but maybe also

Opioid (Narcotic) analgesics

MorphineMorphine Meperidine (Demerol)Meperidine (Demerol) Codeine (Tylenol-3)Codeine (Tylenol-3) Hydromorphone (Dilaudid)Hydromorphone (Dilaudid) Hydrocodone and acetaminophen (Vicodin)Hydrocodone and acetaminophen (Vicodin) Methadone (Dolophine)Methadone (Dolophine) Fentanyl, alfentanil, sufentanil, remifentanilFentanyl, alfentanil, sufentanil, remifentanil

(e.g., sublimaze & duragesic)(e.g., sublimaze & duragesic) Oxycodone (Percodan)Oxycodone (Percodan) Oxycodone and acetaminiphen (Percocet)Oxycodone and acetaminiphen (Percocet) Propoxyphene (Darvon)Propoxyphene (Darvon)

Opioids Inhibit the transmission of pain impulses in Inhibit the transmission of pain impulses in

sensory pathways in the spinal cordsensory pathways in the spinal cord Reduce cortical responses all over the brainReduce cortical responses all over the brain Alter behavioral responses to painAlter behavioral responses to pain

Tolerance & dependence may develop, not Tolerance & dependence may develop, not necessary a sign of abuse or addictionnecessary a sign of abuse or addiction

Opioids

Despite reports of abuse vast majority of Despite reports of abuse vast majority of pain patients use chronically without pain patients use chronically without addiction or dependenceaddiction or dependence

Long-acting much better than short-acting Long-acting much better than short-acting (prevents on-off and sensitization)(prevents on-off and sensitization)

ATC (around-the-clock) preferable to PRN ATC (around-the-clock) preferable to PRN

Non-narcotic analgesics

Salicylates (aspirin–historically there Salicylates (aspirin–historically there were several derivatives)were several derivatives)

Aniline derivatives (Tylenol-Aniline derivatives (Tylenol-acetaminophen) acetaminophen)

Non-steroidal anti-inflammatory Non-steroidal anti-inflammatory agents (NSAIDS)agents (NSAIDS)

NSAIDs

COX 1 & COX 2 inhibitorsCOX 1 & COX 2 inhibitors ibuprofen (Motrin, Advil)ibuprofen (Motrin, Advil) naproxen (Aleve)naproxen (Aleve) diclofenac (Voltaren)diclofenac (Voltaren) indomethacin (Indocin)indomethacin (Indocin) ketorolac (Toradol)ketorolac (Toradol) sulindac (Clinoril)sulindac (Clinoril) mefanamic (Ponstel)mefanamic (Ponstel) piroxicam (Feldene)piroxicam (Feldene) flurbiprofen (Ansaid)flurbiprofen (Ansaid) ketoprofen (Orudis)ketoprofen (Orudis)

Selective COX 2 Selective COX 2 inhibitorsinhibitors

celocoxib (Celebrex)celocoxib (Celebrex) rofecoxib (Vioxx)rofecoxib (Vioxx) valdecoxib (Bextra)valdecoxib (Bextra)

Celebrex & Vioxx

Aspirin and most commonly used NSAIDs Aspirin and most commonly used NSAIDs nonselectively inhibit COX 1 and COX 2nonselectively inhibit COX 1 and COX 2

COX 2 agents have a lower incidence of COX 2 agents have a lower incidence of the ulcerogenic side effects (they increase the ulcerogenic side effects (they increase the risk of heart attack, stroke, and the risk of heart attack, stroke, and clotting disorders, however)clotting disorders, however)

Identified by genetic screen of aspirinIdentified by genetic screen of aspirin side effects include headacheside effects include headache

Therapeutic effects of NSAIDs

AntipyreticAntipyretic Analgesic--low to moderate pain intensity; lack Analgesic--low to moderate pain intensity; lack

unwanted CNS effects of opioidsunwanted CNS effects of opioids

AntiinflammatoryAntiinflammatory

Side effects still include ulcers, blood-thinning. Side effects still include ulcers, blood-thinning. and sensitivityand sensitivity

Only aspirin proven to show anti-MI effects and Only aspirin proven to show anti-MI effects and still in its own category still in its own category

Aniline derivatives–Acetaminophen (Tylenol)

Centrally mediated hypothalamic Centrally mediated hypothalamic stimulation to alter pain perceptionstimulation to alter pain perception

Clinical use–analgesic, weak antipyreticClinical use–analgesic, weak antipyretic No action as anti-inflammatoryNo action as anti-inflammatory

Overdosage is associated with hepatic Overdosage is associated with hepatic necrosis/must be treated within 10 hours - necrosis/must be treated within 10 hours - SERIOUS PROBLEMSERIOUS PROBLEM

Pain adjuvants

Tricyclic antidepressants and SSRIsTricyclic antidepressants and SSRIs

AnticonvulsantsAnticonvulsants CorticosteroidsCorticosteroids Muscle relaxantsMuscle relaxants CapsaicinCapsaicin Local anesthetics (lidocaine, benzocaine)Local anesthetics (lidocaine, benzocaine) Non-pharmacologic therapiesNon-pharmacologic therapies NMDA receptor antagonists (ketamine, DXM, CPP)NMDA receptor antagonists (ketamine, DXM, CPP) Patient-controlled analgesia/epidural analgesiaPatient-controlled analgesia/epidural analgesia

Clinical applications

Review history (drug abuse, allergy)Review history (drug abuse, allergy) Assess level of function and pain levelAssess level of function and pain level

Monitor patient pain relief, toleranceMonitor patient pain relief, tolerance

Level of function after treatmentLevel of function after treatment Surgical treatment of chronic pain is a last Surgical treatment of chronic pain is a last

resort (exception = pumps, stimulators, resort (exception = pumps, stimulators, rhizotomy), usually makes things worserhizotomy), usually makes things worse