Acute Pain and OpioidsAcute Pain and Opioids- - Across the AgesAcross the Ages - -

Dr Pam MacintyreDirector, Acute Pain ServiceRoyal Adelaide Hospital

Across the AgesAcross the Ages

(Bedside) to bench to bedside(Bedside) to bench to bedside since opioids were first used for the since opioids were first used for the

treatment of acute paintreatment of acute pain

Across the life spanAcross the life span from newborn to elderlyfrom newborn to elderly

Newer ‘bench to bedside’ developmentsNewer ‘bench to bedside’ developments clinical advances?clinical advances?

Early Uses of OpiumEarly Uses of Opium

> 5000 years ago> 5000 years ago Sumerians – ‘joy plant’Sumerians – ‘joy plant’

88thth Century BC Century BC Assyrian-Babylonians knew of analgesic, Assyrian-Babylonians knew of analgesic,

hypnotic and sedative propertieshypnotic and sedative properties

Hippocrates (460 Hippocrates (460 – – 377 BC)377 BC) prescribed opium for ‘diseases of women’prescribed opium for ‘diseases of women’

Theophrastus (373 Theophrastus (373 – – 287 BC)287 BC) first documented use for pain relieffirst documented use for pain relief

Prescribing Before the 1800sPrescribing Before the 1800s

Prioreschi et al 1998Prioreschi et al 1998 examined the examined the Hippocratic CorpusHippocratic Corpus used EQ to assess appropriateness of useused EQ to assess appropriateness of use

(compared appropriate use vs. inappropriate)(compared appropriate use vs. inappropriate) concluded that Hippocratic physicians used concluded that Hippocratic physicians used

opium indiscriminatelyopium indiscriminately

Would the same be seen with some drugs Would the same be seen with some drugs given today?given today?

On PhysiciansOn Physicians

Roger Bacon (died 1294)Roger Bacon (died 1294)

““(They are ignorant) of the relation of the (They are ignorant) of the relation of the quantity of noxious drugs and the body, nor quantity of noxious drugs and the body, nor is the method of giving them known, nor is the method of giving them known, nor what quantity for which condition or age”.what quantity for which condition or age”.

The 1800sThe 1800s

SertSertüürner rner isolated morphine from opium (1803 – 1805)isolated morphine from opium (1803 – 1805)

Wood 1853Wood 1853 modified a design of the hypodermic needle modified a design of the hypodermic needle

and syringe made by Fergusonand syringe made by Ferguson injected SC morphine for its ‘local’ effectinjected SC morphine for its ‘local’ effect

Hunter 1856Hunter 1856 effect of SC morphine was systemiceffect of SC morphine was systemic

The 1800s & Early 1900sThe 1800s & Early 1900s

James Paget 1863James Paget 1863 first report of SC morphine for post-first report of SC morphine for post-

operative painoperative pain ¼ to ½ grain (15-30 mg) recommended!¼ to ½ grain (15-30 mg) recommended!

Intrathecal morphine – anecdotal reportsIntrathecal morphine – anecdotal reports Matas 1900Matas 1900 Katawata 1901Katawata 1901 1909-1910 Dundee Royal Infirmary records1909-1910 Dundee Royal Infirmary records

The 1930s to 1940sThe 1930s to 1940s

Advances in opioid chemistry, pharmacologyAdvances in opioid chemistry, pharmacology National Academy of Sciences established National Academy of Sciences established

analgesic program in 1929 analgesic program in 1929 recognition of structure-activity recognition of structure-activity

relationshipsrelationships synthesis of methadone and pentazocinesynthesis of methadone and pentazocine

The 1950sThe 1950s

Innovations in research methodologyInnovations in research methodology mouse hot-plate method mouse hot-plate method guinea pig ileum preparationguinea pig ileum preparation introduction of double-blind studiesintroduction of double-blind studies

Beecher & HoudeBeecher & Houde

Concept of the ‘hypothetical’ opioid receptorConcept of the ‘hypothetical’ opioid receptor drugs exerted effects by interactions with drugs exerted effects by interactions with

receptorsreceptors

The 1950sThe 1950s

Early studies on opioid doseEarly studies on opioid dose 10 mg / 70 kg is ‘optimal dose’10 mg / 70 kg is ‘optimal dose’ avoid high dosesavoid high doses avoid flexibility in dosingavoid flexibility in dosing

Lasagne & Beecher 1954Lasagne & Beecher 1954

The 1960sThe 1960s

Animal model of opioid dependenceAnimal model of opioid dependence

Synthesis of naloxoneSynthesis of naloxone

Patient-controlled analgesiaPatient-controlled analgesia Sechzer 1967Sechzer 1967 Scott 1969Scott 1969

The 1970sThe 1970sPert & Snyder 1973Pert & Snyder 1973 opioid receptors in the brainopioid receptors in the brain

Hughes, Smith & Kosterlitz 1975Hughes, Smith & Kosterlitz 1975 endorphins and enkephalins identifiedendorphins and enkephalins identified

Mather et al 1975 onwardsMather et al 1975 onwards pharmacokinetics & pharmacodynamics pharmacokinetics & pharmacodynamics

of IV, IM and oral opioid administrationof IV, IM and oral opioid administration

Yaksh & Rudy 1976Yaksh & Rudy 1976 analgesia mediated by direct spinal analgesia mediated by direct spinal

action of opioidsaction of opioids

The 1970sThe 1970s

Snyder 1977Snyder 1977 analgesia mediated by opioid receptors in analgesia mediated by opioid receptors in

both brain and spinal cordboth brain and spinal cord

Wang 1978Wang 1978 intrathecal morphine for cancer painintrathecal morphine for cancer pain

Behar et al 1979Behar et al 1979 epidural opioidsepidural opioids

The 1980sThe 1980s

Postoperative epidural morphinePostoperative epidural morphine Bromage et al 1980Bromage et al 1980 Reiz et al 1981Reiz et al 1981 Rawal at al 1981Rawal at al 1981

Acute Pain ServicesAcute Pain Services Ready 1984Ready 1984

The 1990s OnwardsThe 1990s Onwards

Postoperative opioid analgesiaPostoperative opioid analgesia PCAPCA epiduralepidural intrathecalintrathecal intra-articularintra-articular intranasalintranasal sublingual / buccalsublingual / buccal transdermal …………………transdermal …………………

PCA vs IM OpioidsPCA vs IM Opioids

PCA provides (slightly) better analgesia PCA provides (slightly) better analgesia Ballantyne 1993, Waldman 2001Ballantyne 1993, Waldman 2001

PCA is not a ‘one size fits all’ techniquePCA is not a ‘one size fits all’ technique

Epidural vs IM OpioidsEpidural vs IM Opioids

Epidural opioids result in better pain relief Epidural opioids result in better pain relief (opioid + LA better still)(opioid + LA better still)Ballantyne 1998Ballantyne 1998

Epidural opioids Epidural opioids + LA+ LA improve outcome e.g. improve outcome e.g. ↓ ↓ incidence postop chest infectionsincidence postop chest infections more rapid return of GI functionmore rapid return of GI function ↓ ↓ incidence postop MIincidence postop MI

ANZCA 2005ANZCA 2005

Pain at Rest (%)Pain at Rest (%)

0

10

20

30

40

50

60

70

%

All IM PCA Epid

mod/sev

severe

Cashman & Dolan 2002

OpioidsOpioids

Epidural opioid doseEpidural opioid dose Epidural opioid doses Epidural opioid doses with with age age

Ready et al 1987Ready et al 1987

Parenteral opioid dose Parenteral opioid dose PCA IV opioid requirements PCA IV opioid requirements with with age age

Burns et al 1989, Macintyre & Jarvis 1996, Woodhouse Burns et al 1989, Macintyre & Jarvis 1996, Woodhouse & Mather 1997, Gagliese et al 2000& Mather 1997, Gagliese et al 2000

15 20 25 30 35 40 45 50 55 60 65 70

Mean, 110kg

Mean, 70kg

Mean, 40kg

Upper 95% confidence limit, 70kg

Lower 95% confidence limit, 70kg

Patient age (yrs)

200

150

100

50

0

First 24-hrmorphinedose (mg) via IV PCA

Opioid Dose & Patient AgeOpioid Dose & Patient Age

Macintyre & Jarvis, 1996Macintyre & Jarvis, 1996

Physiological Changes & Physiological Changes & Possible Effects on Drug RxPossible Effects on Drug Rx

Cardiac outputCardiac output 0-20%0-20% Smaller initial doseSmaller initial dose

FatFat

Muscle massMuscle mass

10-50%10-50%

20%20%

maintenance dosemaintenance dose

Plasma volumePlasma volume

Total body waterTotal body water↔↔ 10%10%

maintenance dosemaintenance dose

Liver blood flowLiver blood flow 25-40%25-40% maintenance dosemaintenance dose

Renal blood flowRenal blood flow

GFRGFR

Creat. clearanceCreat. clearance

10%/ 10yrs10%/ 10yrs

30-50%30-50%

50-70%50-70%

maintenance dose of maintenance dose of renally excreted renally excreted drugs / drugs / active active metabolitesmetabolites

CNS Sensitivity to OpioidsCNS Sensitivity to Opioids

Scott & Stanski 1987Scott & Stanski 1987 used fentanyl or alfentanil infusions to used fentanyl or alfentanil infusions to

give same EEG stagegive same EEG stage dose required dose required as patient age as patient age 50% decrease in dose from age 20 to 8950% decrease in dose from age 20 to 89 no age-related changes in p’kineticsno age-related changes in p’kinetics

CNS Sensitivity to OpioidsCNS Sensitivity to Opioids

Possible reasons?Possible reasons?

In rats:In rats: reductions in opioid receptor densityreductions in opioid receptor density increases in opioid receptor affinityincreases in opioid receptor affinity age-related changes in synthesis, axonal age-related changes in synthesis, axonal

binding, uptake and receptor binding of binding, uptake and receptor binding of many neurotransmitter systemsmany neurotransmitter systems

Neonates and InfantsNeonates and Infants

Also increased opioid sensitivity Also increased opioid sensitivity

In rats:In rats: developmentally regulated changes in developmentally regulated changes in

opioid receptor expression, function and opioid receptor expression, function and distributiondistribution

alterations in the processing of pain by the alterations in the processing of pain by the developing nervous systemdeveloping nervous system

increased sensitivity to opioids in rat pupsincreased sensitivity to opioids in rat pups

Neonates and InfantsNeonates and Infants

Clinically: Clinically: postop morphine requirements postop morphine requirements age age in older children average PCA morphine in older children average PCA morphine

requirements correlate with age requirements correlate with age

Extended-release Epidural Extended-release Epidural MorphineMorphine

48 hour duration48 hour duration

Single dose (no epidural catheter)Single dose (no epidural catheter)

Lumbar administrationLumbar administration

Not titratableNot titratable

Should not mix with local anaestheticsShould not mix with local anaesthetics 3- 4% respiratory depression 3- 4% respiratory depression

Iontophoretic TD FentanylIontophoretic TD Fentanyl

fixed dose delivered only when system is fixed dose delivered only when system is activatedactivated

is as effective as IV morphine PCAis as effective as IV morphine PCA is as effective as is as effective as I mg bolus doseI mg bolus dose morphine morphine

The Problem with OpioidsThe Problem with Opioids

enormous interpatient variationenormous interpatient variation may not be effective for all types of may not be effective for all types of

acute pain or in all situationsacute pain or in all situations side effectsside effects tolerancetolerance opioid-induced painopioid-induced pain inadequate monitoring and titration inadequate monitoring and titration

regardless of techniqueregardless of technique

The Next 30 The Next 30 –– 40 Years 40 Years

‘‘better’ opioids?better’ opioids? better routes of delivery?better routes of delivery? better treatment of side effects?better treatment of side effects?

new antiemeticsnew antiemetics incidence with naloxoneincidence with naloxone

use of adjuvants with opioids?use of adjuvants with opioids? ketamineketamine F13640F13640

better non-opioid analgesics?better non-opioid analgesics?