Long-acting opioids in obstetric analgesia and the newborn

1. Long-acting opioids in obstetric analgesia and the newborn Merja Kokki MD, PhD Department of Anaesthesiology and Intensive Care, Kuopio University Hospital, School of Medicine, University of Eastern Finland

2. Contents Placenta and placental drug permeability Tramadol Hydromorphone Oxycodone Morphine/diamorphine Opioid dependent mother Pharmacogenetics Closure

3. Take home message Opioids are moderately efficacious in labour pain Optimal doses and dosing time not known Pethidine use will/should decrease Oxycodone is a useful opioid in labour pain The drug effect on newborn must be followed

4. Placenta In humans: haemomonochorial placenta single layer of trophoblast tissue separates the mother's blood from the blood capillaries of the foetus

5. Placentaldrugpermeability Passive diffusion concentration gradient lipid solubility flow dependent transfer Diffusion of ions as non-ionized base most of the opioids

6. Physicochemicalproperties of opioids

7. Drugs and the effects to the newborn • Direct effects • Placental transfer • Indirect effects • Maternal physiology and biochemistry

8. Equilibriumdistributionacrossplacenta pH gradient mother – fetus Fetal plasma pH lower than maternal Free base concentrates to the fetal side (ion trapping) Acidotic fetus is exposed to basic drugs local anaesthetics and opioids

9. Equilibriumdistributionacrossplacenta • Protein binding • Fetal plasma protein content increases at term • Albumin • Little transplacental gradient • α1-acid glycoprotein (AAG) • Lower in fetus • Binding higher in maternal than fetal side

10. Equilibriumdistributionacrossplacenta • Equilibration takes longer time in fetus than in maternal tissue • Fetal exposure is dependent on • Blood flow • Equilibrium ratios • Duration of exposure

11. Pethidine, meperidine • Maternal T½ 2-3 h, neonatal T½ 16-22h • Active metabolites: norpethidine • Crosses placenta slowly • Fetal/matenal ratio does not correlate with dose-delivery interval • Fetal effect at maximum 3 hours after maternal administration

12. Pethidine: adverseeffects

13. The relationshipbetweendose-deliveryinterval and neonatalurinaryexcretion of pethidine and norpethidine Kuhnert et al. 1979

14. Obstetric analgesia: a comparison of patient-controlled meperidine, remi-fentanil, and fentanyl in labour Douma et al. BJA 2010 • PCA • Pethidine 50 mg loading, 5 mg bolus, lock out 10 min (n= 53) • Remifentanil 40 µg loading, 40 µg bolus, lock out 2 min, max 1200 µg/h (n= 52) • Fentanyl 50 µg loading, 20 µg bolus, lock out 5 min, max 240 µg/h (n=54)

15. Obstetric analgesia: a comparison of patient-controlled meperidine, remifentanil, and fentanyl in labour * * p<0.05 when compared to the baseline

16. Effect of pethidine administered during the first stage of labor on the acid-base status at birth.Sosa et al. Eur J Obstet Gynecol Reprod Biol 2006 • 383 arterial blood cord samples • Pethidine group • Lower pH and bicarbonate levels • higher pCO2 levels were found in the. • pH < 7.12, OR: 8.59, 95% C.I. 3.29, 22.46 • The highest frequency of acidosis with pethidine-delivery interval 5 h.

17. Parenteral opioids for maternal pain relief in labour 54 studies, > 7000 women Poor quality of studies 2/3 women reported moderate/severe pain and poor/moderate pain relief after opioid treatment Ullman et al. 2010

18. Parenteral opioids for maternal pain relief in labour Ullman et al. 2010 Opioids provide some pain relief Adverse effects drowsiness, nausea and vomiting Insufficient evidence to assess safety of opioids in labour pain

19. Tramadol • Prodrug, with active metabolite O-desmethyl tramadol=M1 • Affects both opioid receptor and prevents serotonin uptake • CYP 2D6 substrate • Polymorphisms: poor metaboliser, no/poor drug effect; extensive metaboliser, marked drug effect, adverse effects • Drug interactions (SSRI)

20. Different pharmacokinetics of tramadol in mothers treated for labour pain and in their neonates Claahsen-van der Grinten et al. Eur J Clin Pharmacol 2005

21. A comparison of tramadol and pethidine analgesia on the duration of labour: A randomised clinical trialKhooshideh et al. Australian and New Zealand Journal of Obstetrics and Gynaecology 2009 Pethidine 50 mg vs tramadol 100mg N= 160 Shorter delivery time with tramadol 165 min vs. 223 min

22. The Risk of Cesarean Delivery with Neuraxial Analgesia Given Early versus Late in Labor Wong et al. N Engl J Med 2005 CSE (n=366) vs. hydromorphone 1 + 1 mg (n=362) No differences in labour outcome * <0.001

23. Oxycodone • µ-opioid agonist • T½ 3-4 h • Metbolism: CYP 3A4 and CYP 2D6 • Oxymorphone, noroxycodone, noroxymorphone • Hodge 1965: No advantages when comparing to pethidine and morphine • Data quality poor

24. Oxycodone in early labour pain • Oxycodone 1 mg i.v. ad. 5 mg • Pharmacokinetic/dynamic study P-Oxycodone: • Umbilical artery: 3,2 (0,1–14) mg/l • Umbilical vein 2,7 (0,0–14) mg/l • Mother 3,0 (0,1–15) mg/l • Positive correlation (r = 0,98 ja 0,96, p = 0,001)

25. Morphine and diamorphine (heroin) • Diamorphine: prodrug 3,6-diacetyl ester of morphine T½ <10 min • Parenteral use • Morphine T ½ 2-3 h • Intrathecaluse • M6-glucuronide, and M3-glucuronide • Renalexcretion

26. Addition of low-dose morphine to intrathecalbupivacaine/ sufentanillabour analgesia: A randomised controlled study Morphine 50 or 100 µg or saline added to bupivacaine 1,25 mg + sufentanil 5 µg Hein et al 2010 IJOA

27. Addition of low-dose morphine to intrathecalbupivacaine/ sufentanillabour analgesia: A randomised controlled study

28. Diamorphine for pain relief in labour pain: a randomised controlled trial comparing intramuscular and patient controlled analgesia McInnes et al. BJOG 2004 • PCA Diamorphine, loading 1.2 mg, lock out 5 min., max 1.8 mg/h vs. 5-7.5 mg i.m

29. Diamorphine for pain relief in labour pain: a randomised controlled trial comparing intramuscular and patient controlled analgesiaMcInnes et al. BJOG 2004

30. Opioid dependentmother on maintenancetreatment and labour pain relief • Buprenorphine • No difference in pain or analgesia during labour when compared to controls • After labour/CS increased pain • After CS increased need of analgesics Meyer et al. Eur J Pain 2010 • Methadone • Similar analgesic needs and response during labor than controls, but require 70% more opiate analgesic after CS Meyer et al. Obst Gyn 2007

31. Pharmacogenetics in labour analgesia • Single nucleotide polymorphism in μ-opioid receptor gene (OPRM1 gene) • C.304A>G2 (118A>G) • May affect individual response to opioid analgesia

32. Observational study of the effect of µ-opioid receptor genetic polymorphism on intrathecal opioid labor analgesia and post-cesarean delivery analgesia Wong et al. IJOA 2010 • Postoperative analgesia CS: i.t morphine 150 μg • Labour analgesia: bupivacaine + fentanyl PCEA

33. Duration of fentanyl labour analgesia Wong et al. IJOA 2010

34. Need of pomorphineafter CS

35. Conclusion • Optimal doses of longacting opioids and dosing times are not known • Pethidine use will decrease • Oxycodone is a feasible opioid in early labour pain • The drug effect in newborn must be followed • Pharmacogenetics may change future drug therapies