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

Duration of fentanyl labour Duration of fentanyl labour analgesiaanalgesia

Wong et al. IJOA 2010

Need of po morphine after Need of po morphine after CSCS

ConclusionConclusion• 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