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Long-acting opioids in Long-acting opioids in obstetric analgesia and the obstetric analgesia and the
newbornnewborn
Merja Kokki MD, PhDMerja Kokki MD, PhD
Department of Anaesthesiology and Intensive Care, Kuopio Department of Anaesthesiology and Intensive Care, Kuopio University Hospital, School of Medicine, University of Eastern University Hospital, School of Medicine, University of Eastern
FinlandFinland
ContentsContents
• Placenta and placental drug permeability• Tramadol• Hydromorphone• Oxycodone• Morphine/diamorphine• Opioid dependent mother• Pharmacogenetics• Closure
Take home messageTake 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
PlacentaPlacenta
• In humans: haemomonochorial placenta– single layer of trophoblast tissue separates the
mother's blood from the blood capillaries of the foetus
Placental drug permeabilityPlacental 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 opioidsPhysicochemical 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 AAG
Oxycodone 315 16.2 45 Albumin
Buprenorphine 467 8.4 96 -, -globulins
Drugs and the effects to the newbornDrugs and the effects to the newborn
• Direct effects– Placental transfer
• Indirect effects– Maternal physiology and biochemistry
Equilibrium distribution across Equilibrium distribution across placentaplacenta
• 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 Equilibrium distribution across placentaplacenta
• 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 placentaEquilibrium 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, meperidinePethidine, 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
Pethidine: adverse effectsPethidine: adverse effectsFetal 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 The relationship between dose-delivery interval and neonatal urinary excretion interval and neonatal urinary excretion
of pethidine and norpethidineof pethidine and norpethidine
Kuhnert et al. 1979
Obstetric analgesia: a comparison of Obstetric analgesia: a comparison of patient-controlled meperidine, remi-patient-controlled meperidine, remi-fentanil, and fentanyl in labourfentanil, 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 patient-Obstetric analgesia: a comparison of patient-controlled meperidine, remifentanil, and controlled meperidine, remifentanil, and
fentanyl in labourfentanyl 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 Parenteral opioids for maternal pain relief in labourrelief 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 Parenteral opioids for maternal pain relief in labourpain 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
TramadolTramadol
• 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 Different pharmacokinetics of tramadol in mothers treated for labour pain and in their neonatestreated for labour pain and in their neonates
A comparison of tramadol and pethidine analgesia A comparison of tramadol and pethidine analgesia on the duration of labour: A randomised clinical trialon the duration of labour: A randomised clinical trialKhooshideh et al. Khooshideh et al. Australian and New Zealand Journal of Obstetrics and GynaecologyAustralian and New Zealand Journal of Obstetrics and Gynaecology 2009 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 The Risk of Cesarean Delivery with Neuraxial Analgesia Given Early versus Late in LaborAnalgesia Given Early versus Late in Labor
• CSE (n=366) vs. hydromorphone 1 + 1 mg (n=362)
• No differences in labour outcome
• * <0.001
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±0.07Wong et al. N Engl J Med 2005
OxycodoneOxycodone
• 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 Oxycodone in early labour painpain
• 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 Morphine and diamorphine (heroin) (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 Addition of low-dose morphine to intrathecal bupivacaine/ sufentanil labour analgesia: A bupivacaine/ sufentanil labour analgesia: A
randomised controlled studyrandomised 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 Addition of low-dose morphine to intrathecal bupivacaine/ sufentanil labour intrathecal bupivacaine/ sufentanil labour analgesia: A randomised controlled studyanalgesia: A randomised controlled study
Diamorphine for pain relief in labour pain: a Diamorphine for pain relief in labour pain: a randomised controlled trial comparing intramuscular randomised controlled trial comparing intramuscular and patient controlled analgesiaand patient controlled analgesia McInnes et al. BJOG 2004 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 Diamorphine for pain relief in labour pain: a randomised controlled trial comparing randomised controlled trial comparing intramuscular and patient controlled analgesiaintramuscular and patient controlled analgesia McInnes et al. BJOG 2004McInnes et al. BJOG 2004
Opioid dependent mother on Opioid dependent mother on maintenance treatment and labour maintenance treatment and labour
pain reliefpain 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 Pharmacogenetics in labour analgesiaanalgesia
• Single nucleotide polymorphism in μ-opioid 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