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 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 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 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 pco 2 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 Pain (VRS) at 1 st pain request Pain at 2 nd request Duration of 1 st analgesia CSE 8 (7-9) 5 (3-7) 95 (73-119) Opioid 8 (7-9) 8 * (7-9) 108 * (80-144) Vomiting 7/366 62/362 * Wong et al. N Engl J Med 2005 Umbilical vein ph Umbilical artery ph 7.30±0.06 7.30±0.06 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 μ- opioid receptor gene (OPRM1 gene) C.304A>G 2 (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