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
Contents
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Placenta and placental drug permeability
Tramadol
Hydromorphone
Oxycodone
Morphine/diamorphine
Opioid dependent mother
Pharmacogenetics
Closure
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
Placenta
• In humans: haemomonochorial placenta
– single layer of trophoblast tissue separates the
mother's blood from the blood capillaries of the
foetus
Placental drug permeability
• Passive diffusion
– concentration gradient
– lipid solubility
– flow dependent transfer
• Diffusion of ions as non-ionized base
– most of the opioids
Physicochemical properties of opioids
Molecular
weight
pKa base Protein
group
binding
(%)
Principal
binding
protein
Morphine
285
7.9
30
Albumin
Pethidine
247
8.5
30-65
AAG
Methadone
309
9.3
60-90
AAG
Oxycodone
315
16.2
45
Albumin
Buprenorphine
467
8.4
96
-, globulins
Drugs and the effects to the newborn
• Direct effects
– Placental transfer
• Indirect effects
– Maternal physiology and biochemistry
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
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
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
Pethidine, meperidine
• Maternal T½ 2-3 h, neonatal T½ 16-22h
• Active metabolites: norpethidine
– Crosses placenta slowly
– Fetal/matenal ratio does not correlate with dosedelivery interval
• Fetal effect at maximum 3 hours after
maternal administration
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
The relationship between dose-delivery
interval and neonatal urinary excretion
of pethidine and norpethidine
Kuhnert et al. 1979
Obstetric analgesia: a comparison of
patient-controlled meperidine, remifentanil, 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
Obstetric analgesia: a comparison of patientcontrolled meperidine, remifentanil, and
fentanyl in labour
*
* p<0.05 when compared to the baseline
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.
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
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
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)
Different pharmacokinetics of tramadol in mothers
treated for labour pain and in their neonates
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
The Risk of Cesarean Delivery with Neuraxial
Analgesia Given Early versus Late in Labor
• CSE (n=366) vs.
hydromorphone 1
+ 1 mg (n=362)
• No differences in
labour outcome
• * <0.001
Wong et al. N Engl J Med 2005
CSE
Opioid
Pain (VRS) at 1st
pain request
8
(7-9)
8
(7-9)
Pain at 2nd
request
5
(3-7)
8 *
(7-9)
Duration of 1st
analgesia
95
(73-119)
108 *
(80-144)
Vomiting
7/366
62/362 *
Umbilical vein
pH
7.30±0.06
7.30±0.06
Umbilical artery
pH
7.24±0.08
7.23±0.07
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
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)
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
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
Hein et al 2010 IJOA
Addition of low-dose morphine to
intrathecal bupivacaine/ sufentanil labour
analgesia: A randomised controlled study
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
Diamorphine for pain relief in labour pain: a
randomised controlled trial comparing
intramuscular and patient controlled analgesia
McInnes et al. BJOG 2004
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
Pharmacogenetics in labour
analgesia
• Single nucleotide polymorphism in μopioid receptor gene (OPRM1 gene)
• C.304A>G2 (118A>G)
• May affect individual response to
opioid analgesia
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
Duration of fentanyl labour
analgesia
Wong et al. IJOA 2010
Need of po morphine after
CS
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