Acute Pain and Opioids - Across the Ages -

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Acute Pain and Opioids- Across the Ages -
Dr Pam Macintyre Director, Acute Pain
Service Royal Adelaide Hospital
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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?

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Early Uses of Opium

• gt 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

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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?

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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.

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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

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The 1800s Early 1900s

• James Paget 1863
• first report of SC morphine for post-operative
  pain
• ¼ to ½ grain (15-30 mg) recommended!
• Intrathecal morphine anecdotal reports
• Matas 1900
• Katawata 1901
• 1909-1910 Dundee Royal Infirmary records

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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

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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

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The 1950s

• Early studies on opioid dose
• 10 mg / 70 kg is optimal dose
• avoid high doses
• avoid flexibility in dosing
• Lasagne Beecher 1954

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The 1960s

• Animal model of opioid dependence
• Synthesis of naloxone
• Patient-controlled analgesia
• Sechzer 1967
• Scott 1969

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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

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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

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The 1980s

• Postoperative epidural morphine
• Bromage et al 1980
• Reiz et al 1981
• Rawal at al 1981
• Acute Pain Services
• Ready 1984

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The 1990s Onwards

• Postoperative opioid analgesia
• PCA
• epidural
• intrathecal
• intra-articular
• intranasal
• sublingual / buccal
• transdermal

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PCA vs IM Opioids

• PCA provides (slightly) better analgesia
• Ballantyne 1993, Waldman 2001
• PCA is not a one size fits all technique

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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

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Pain at Rest ()
Cashman Dolan 2002
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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

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Opioid Dose Patient Age
200 150 100 50 0
Upper 95 confidence limit, 70kg
First 24-hr morphine dose (mg) via IV PCA
Mean, 110kg
Mean, 70kg
Mean, 40kg
Lower 95 confidence limit, 70kg
15 20 25 30 35 40 45
50 55 60 65 70
Patient age (yrs)
Macintyre Jarvis, 1996
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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 ? ? 10 ? 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
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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 pkinetics

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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

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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

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Neonates and Infants

• Clinically
• postop morphine requirements ? age
• in older children average PCA morphine
  requirements correlate with age

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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

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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

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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

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The Next 30 40 Years

• better opioids?
• better routes of delivery?
• better treatment of side effects?
• new antiemetics
• ? incidence with naloxone
• ? use of adjuvants with opioids?
• ketamine
• F13640
• better non-opioid analgesics?