Acute Pain and Opioids
- Across the Ages -
Dr Pam Macintyre
Director, Acute Pain Service
Royal Adelaide Hospital
Across the Ages
(Bedside) to bench to bedside
 since opioids were first used for the
treatment of acute pain
Across the life span
 from newborn to elderly
Newer ‘bench to bedside’ developments
 clinical advances?
Early Uses of Opium
> 5000 years ago
 Sumerians – ‘joy plant’
8th Century BC
 Assyrian-Babylonians knew of analgesic,
hypnotic and sedative properties
Hippocrates (460 – 377 BC)
 prescribed opium for ‘diseases of women’
Theophrastus (373 – 287 BC)
 first documented use for pain relief
Prescribing Before the 1800s
Prioreschi et al 1998

examined the Hippocratic Corpus
used EQ to assess appropriateness of use
(compared appropriate use vs. inappropriate)


concluded that Hippocratic physicians used
opium indiscriminately
Would the same be seen with some drugs given
today?
On Physicians
Roger Bacon (died 1294)
“(They are ignorant) of the relation of the
quantity of noxious drugs and the body, nor
is the method of giving them known, nor
what quantity for which condition or age”.
The 1800s
Sertürner
 isolated morphine from opium (1803 – 1805)
Wood 1853
 modified a design of the hypodermic needle
and syringe made by Ferguson
 injected SC morphine for its ‘local’ effect
Hunter 1856
 effect of SC morphine was systemic
The 1800s & Early 1900s
James Paget 1863
 first report of SC morphine for postoperative pain
 ¼ to ½ grain (15-30 mg) recommended!
Intrathecal morphine – anecdotal reports
 Matas 1900
 Katawata 1901
 1909-1910 Dundee Royal Infirmary records
The 1930s to 1940s
Advances in opioid chemistry, pharmacology

National Academy of Sciences established
analgesic program in 1929

recognition of structure-activity
relationships

synthesis of methadone and pentazocine
The 1950s
Innovations in research methodology
 mouse hot-plate method
 guinea pig ileum preparation
 introduction of double-blind studies
Beecher & Houde
Concept of the ‘hypothetical’ opioid receptor
 drugs exerted effects by interactions with
receptors
The 1950s
Early studies on opioid dose

10 mg / 70 kg is ‘optimal dose’

avoid high doses

avoid flexibility in dosing
Lasagne & Beecher 1954
The 1960s
Animal model of opioid dependence
Synthesis of naloxone
Patient-controlled analgesia
 Sechzer 1967
 Scott 1969
The 1970s
Pert & Snyder 1973
 opioid receptors in the brain
Hughes, Smith & Kosterlitz 1975
 endorphins and enkephalins identified
Mather et al 1975 onwards
 pharmacokinetics & pharmacodynamics
of IV, IM and oral opioid administration
Yaksh & Rudy 1976
 analgesia mediated by direct spinal
action of opioids
The 1970s
Snyder 1977
 analgesia mediated by opioid receptors in
both brain and spinal cord
Wang 1978
 intrathecal morphine for cancer pain
Behar et al 1979
 epidural opioids
The 1980s
Postoperative epidural morphine
 Bromage et al 1980
 Reiz et al 1981
 Rawal at al 1981
Acute Pain Services
 Ready 1984
The 1990s Onwards
Postoperative opioid analgesia
 PCA
 epidural
 intrathecal
 intra-articular
 intranasal
 sublingual / buccal
 transdermal …………………
PCA vs IM Opioids

PCA provides (slightly) better analgesia
Ballantyne 1993, Waldman 2001
PCA is not a ‘one size fits all’ technique
Epidural vs IM Opioids

Epidural opioids result in better pain relief
(opioid + LA better still)
Ballantyne 1998

Epidural opioids + LA improve outcome e.g.
 ↓ incidence postop chest infections
 more rapid return of GI function
 ↓ incidence postop MI
ANZCA 2005
Pain at Rest (%)
70
60
Cashman &
Dolan 2002
50
%
40
30
20
mod/sev
10
severe
0
All
IM
PCA
Epid
Opioids
Epidural opioid dose
 Epidural opioid doses  with  age
Ready et al 1987
Parenteral opioid dose
 PCA IV opioid requirements  with  age
Burns et al 1989, Macintyre & Jarvis 1996, Woodhouse
& Mather 1997, Gagliese et al 2000
Opioid Dose & Patient Age
200
Upper 95% confidence limit, 70kg
150
First 24-hr Mean, 110kg
morphine100
dose (mg)
via IV PCA
Mean, 70kg
Mean, 40kg
50
Lower 95% confidence limit, 70kg
0
15
20
Macintyre & Jarvis, 1996
25
30
35
40
45
50
Patient age (yrs)
55
60
65
70
Physiological Changes &
Possible Effects on Drug Rx
Cardiac output
 0-20%
Smaller initial dose
Fat
Muscle mass
 10-50%
 20%
 maintenance dose
Plasma volume
Total body water
↔
 maintenance dose
Liver blood flow
 25-40%
 maintenance dose
Renal blood flow
GFR
Creat. clearance
 10%/ 10yrs
 30-50%
 50-70%
 maintenance dose of
renally excreted
drugs /  active
metabolites
 10%
CNS Sensitivity to Opioids
Scott & Stanski 1987

used fentanyl or alfentanil infusions to
give same EEG stage

dose required  as patient age 

50% decrease in dose from age 20 to 89

no age-related changes in p’kinetics
CNS Sensitivity to Opioids
Possible reasons?
In rats:

reductions in opioid receptor density

increases in opioid receptor affinity

age-related changes in synthesis, axonal
binding, uptake and receptor binding of
many neurotransmitter systems
Neonates and Infants
Also increased opioid sensitivity
In rats:

developmentally regulated changes in
opioid receptor expression, function and
distribution

alterations in the processing of pain by the
developing nervous system

increased sensitivity to opioids in rat pups
Neonates and Infants
Clinically:


postop morphine requirements  age
in older children average PCA morphine
requirements correlate with age
Extended-release Epidural
Morphine

48 hour duration

Single dose (no epidural catheter)

Lumbar administration

Not titratable

Should not mix with local anaesthetics

3- 4% respiratory depression
Iontophoretic TD Fentanyl

fixed dose delivered only when system is
activated

is as effective as IV morphine PCA

is as effective as I mg bolus dose morphine
The Problem with Opioids

enormous interpatient variation

may not be effective for all types of
acute pain or in all situations

side effects

tolerance

opioid-induced pain

inadequate monitoring and titration
regardless of technique
The Next 30 – 40 Years

‘better’ opioids?

better routes of delivery?

better treatment of side effects?



 use of adjuvants with opioids?



new antiemetics
 incidence with naloxone
ketamine
F13640
better non-opioid analgesics?