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

2. 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?

3. Early Uses of Opium > 5000 years ago  Sumerians – ‘joy plant’ 8 th 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

4. 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?

5. 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”.

6. 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

7. 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

8. 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

9. 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

10. The 1950s Early studies on opioid dose  10 mg / 70 kg is ‘optimal dose’  avoid high doses  avoid flexibility in dosing Lasagne & Beecher 1954

11. The 1960s Animal model of opioid dependence Synthesis of naloxone Patient-controlled analgesia  Sechzer 1967  Scott 1969

12. 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

13. 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

14. The 1980s Postoperative epidural morphine  Bromage et al 1980  Reiz et al 1981  Rawal at al 1981 Acute Pain Services  Ready 1984

15. The 1990s Onwards Postoperative opioid analgesia  PCA  epidural  intrathecal  intra-articular  intranasal  sublingual / buccal  transdermal …………………

16. PCA vs IM Opioids  PCA provides (slightly) better analgesia Ballantyne 1993, Waldman 2001 PCA is not a ‘one size fits all’ technique

17. 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

18. Pain at Rest (%) Cashman & Dolan 2002

19. 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

20. 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-hr morphine dose (mg) via IV PCA Opioid Dose & Patient Age Macintyre & Jarvis, 1996

21. 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

22. 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

23. 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

24. 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

25. Neonates and Infants Clinically:  postop morphine requirements  age  in older children average PCA morphine requirements correlate with age

26. 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

27. 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

28. 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

29. 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?