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
A haemomonochorial placenta is a type of haemochorial placenta (placenta where the chorion, or membrane enclosing the foetus, comes in direct contact with the mother's blood) where a single layer of trophoblast tissue separates the mother's blood from the blood capillaries of the foetus.

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

6. Physicochemical properties of opioids
Molecular weight
pKa base group
Protein binding
(%)
Principal binding protein
Morphine
285
7.9 30
Albumin
Pethidine
247
8.5
30-65
AAG
Methadone
309
9.3
60-90
Oxycodone
315
16.2 45
Buprenorphine
467
8.4 96
-, -globulins

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

8. Equilibrium distribution across placenta
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
Because fetal pH is usually slightly more acidic than the
maternal pH, weak bases are more likely to cross the placenta.
However, once crossing the placenta and making
contact with relatively acidic fetal blood, these molecules
become more ionized; this phenomenon is known as “ion
trapping” (Loebstein et al., 1997). Lipid soluble drugs will
also pass more readily through cell membranes and, therefore,
can pass easily to the placenta. For example, antibiotics
and opiates are highly lipid soluble and pass readily to
the placenta (Kraemer, 1997).

9. Equilibrium distribution across placenta
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
The molecular weight of a drug also has an impact on
its ability to cross the placenta. As a general rule, the larger
a drug molecule, the higher the molecular weight. As such,
drugs with a lower molecular weight (500 g/mol) cross
the placenta readily, while drugs with a molecular weight
between 600 and 1000 cross at a slower rate. A few drugs
with a high molecular weight (1,000 g/mol), such as heparin
and insulin, fail to cross the placenta in significant
amounts (Kraemer, 1997).
Transplacental transfer of drugs increases in the third
trimester due to increased maternal and placental blood
flow, and decreased thickness and increased surface area of
the placenta. Ion trapping may produce drug concentrations
in the fetus that exceed that of the mother. However,
for most drugs the fetal blood concentrations tend to be 50
to 100% of the maternal blood concentrations (Yankowitz
& Niebyl, 2001).

10. Equilibrium distribution across placenta
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: adverse effects
Fetal effects
Reduced
Muscular activity
Aortic blood flow
Oxygen saturation
Short term heart rate variation
Neonatal effects
Depressed
Apgar scores
Respiration
Neurobehavioural scores
Muscle tone and suckling
A detrimental effect on
breastfeeding

13. The relationship between dose-delivery interval and neonatal urinary excretion of pethidine and norpethidine
Kuhnert et al. 1979

14. Obstetric analgesia: a comparison of patient-controlled meperidine, remi-fentanil, and fentanyl in labour
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)
Douma et al. BJA 2010

15. Obstetric analgesia: a comparison of patient-controlled meperidine, remifentanil, and fentanyl in labour *
Satisfaction score was best with remifentanil, 8 and equally good with pethidine and fentanyl. More oxygen desaturation less than 95% with remifentanil 37/50 vs 16/48 pethdine and 30/54 with fentanyl.
* p<0.05 when compared to the baseline

16. 383 arterial blood cord samples Pethidine group
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
Opioids provide some pain relief
Adverse effects drowsiness, nausea and vomiting
Insufficient evidence to assess safety of opioids in labour pain
Ullman et al. 2010

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
Pharmacokinetic profile of tramadol (upper panels) and its
non-stereoselective metabolite M1 (lower panels) in a population of
mothers (n=22) treated with 100–250 mg tramadol (i.m.) for pain
relief during labour and their neonates (n=22). The terminal
elimination curves (fat lines) during the first 24 h post-partum and
the apparent elimination kinetics of early distribution into a second
compartment (dashed lines) were estimated on a population kinetic
basis. Individual data (filled circles) and mean values (open squares)
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 trial Khooshideh 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
CSE (n=366) vs. hydromorphone mg (n=362)
No differences in labour outcome
* <0.001
CSE
Opioid
Pain (VRS) at 1st pain request 8
(7-9)
Pain at 2nd request 5
(3-7)
8 *
Duration of 1st analgesia 95
(73-119)
108 *
(80-144)
Vomiting
7/366
62/362 *
Umbilical vein pH
7.30±0.06
Umbilical artery pH
7.24±0.08
7.23±0.07
Wong et al. N Engl J Med 2005

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
Intrathecal use
M6-glucuronide, and M3-glucuronide
Renal excretion

26. Addition of low-dose morphine to intrathecal bupivacaine/ sufentanil labour analgesia: A randomised controlled study
Morphine 50 or 100 µg or saline added to bupivacaine 1,25 mg + sufentanil 5 µg
CSE analgesia, epidural not used during the study
Hein et al 2010 IJOA

27. Addition of low-dose morphine to intrathecal bupivacaine/ sufentanil labour 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 mg i.m

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

30. Opioid dependent mother on maintenance treatment 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. Postoperative analgesia CS: i.t morphine 150 μg
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 po morphine after 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