Pharmacologic Options Peripartum Analgesia Day 3. Inhalational agents Sedatives Anti-emetics Reversal Agents Postpartum Analgesia

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2 Pharmacologic Options Peripartum Analgesia Day 3 Inhalational agents Sedatives Anti-emetics Reversal Agents Postpartum Analgesia 123

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4 N=N=O F H F C C* Br F Cl F F F Cl C* C O C H H F F Nitrous Oxide Halothane Enflurane F H F F C C* O C H F Cl F Isoflurane F F H H C F C O C F F C H F F Sevoflurane F H F F C C* O C H F F F Desflurane 125

5 Nitrous Oxide A weak non-volatile inhalational anesthetic agent with very poor solubility (blood:gas solubility coefficient) Mechanism of action: CNS depressant thought to alter pain perception through descending spinal cord pathways Minimum aveolar concentration (MAC) 104% = low potency Pregnancy associated with a 20-35% reduction in MAC at term Side effects: dizziness, nausea, sedation, hypoventilation Loss of consciousness from oversedation: 0.4% with 50:50 mix Sedation potentiated by prior parenteral opioid use 126

6 Nitrous Oxide Benefits Safe for fetus/neonate as poor lipid solubility therefore transfer low and onset of spontaneous respirations at birth quickly eliminates residual N 2 O No effect on uterine tone Inexpensive Minimal toxicity, minimal cardiac depression No known effect on breastfeeding i.e. relatively benign 127

7 Uptake and Distribution Curve N 2 O Poor lipid solubility = limited uptake by tissues therefore rapid rise of lung concentration > blood > brain Low potency adds inherent safety 128

8 Entonox aka laughing gas A 50:50 mixture N 2 O : oxygen Used by about 35% of women in Canada, higher usage where epidural analgesia not available Very weak analgesia, one study - no benefit over air; but many women obtain some relief Psychological benefit likely real: creates focus on breathing technique Breathing at start of contraction to maximize peak N 2 O concentration (50s) at peak of contraction Avoid hyperventilation as shifts maternal oxyhemoglobin dissociation curve to left and reduces fetal uptake O 2 129

9 Entonox Safety Measures Scavenging system necessary to prevent exposure of health professionals: Prolonged repeated exposure associated with reduction in methionine synthetase production: Vit B12 Possible association with miscarriage in allied health professionals Demand valve set-up to reduce room contamination Patient ONLY administered Mouthpiece better than mask Regular equipment maintenance Greenhouse gas! (<2% world production N 2 O) 130

10 Volatile Anesthetics All ether-related except halothane (an alkane) Modern: sevoflurane, desflurane All halogenated compounds that are stored as liquid and dispersed via a vapourizer into common gas flow (air, oxygen, N 2 O are the carriers) Direct uterine smooth muscle relaxants > 0.8 MAC Agent MAC % Blood-Gas Solubility Concerns Desflurane (N 2 O 0.47) Sevoflurane (ct isoflurane 1.4) Pungent, poorly tolerated awake Compound A formation 131

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12 Sevoflurane for Labour Analgesia 2007: optimal concentration for sevoflurane for labour analgesia determined to be 0.8% (in oxygen) 2007: 32 parturients randomized to sevoflurane 0.8% vs Entonox using self as study controls Better pain relief scores More sedation, which some women liked No evidence impaired airway reflexes 1985: isoflurane 0.75% compared with Entonox and found better analgesia, poorly tolerated due to pungency Same concerns regarding labour room pollution as N 2 O Too few cases to decide about maternal safety 133

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14 Benzodiazepines Most commonly used for sedation and anxiolysis May affect neonatal neurobehavioural scores Useful to reduce excessive anxiety peri-procedure: Anxiety is linked to increased pain Anxiety is linked to increased nausea/vomiting Hepatic metabolism Highly protein bound Receptor: indirect GABA A enhance effects of GABA Pregnancy Class D: 1 st trimester cleft lip/palate 3 rd trimester neonatal benzodiazpine withdrawal syndrome 136

15 GABA A Receptor Benzodiazepines é frequency of opening Barbiturates é duration GABA is the primary inhibitory neurotransmitter in the CNS GABA-receptor allows Cl - to cross into the cell, hyperpolarizing the membrane and inhibiting neural transmission Lipid bilayer of the neural membrane 137

16 Benzodiazepines Effects Sedation Hypnosis Anxiolysis Anti-convulsant Amnesia Muscle relaxant Co-analgesic Side-effects Drowsiness Amnesia Depression Balance Dependence Cognitive impairment Paradoxical reactions Respiratory Depression (insignificant in healthy adult if sole agent; enhances respiratory depressant effects of coadministered opioid) 138

17 Specific Benzodiazepines Drug Dose and Duration Side-effects Midazolam Lorazepam Diazepam 0.15 mcg/kg IV 40 minutes Elimination T½ 2-3h 1-2 mg sl 4-6 hours Elimination T½ 12h 10 mg po 4-6 hours Elimination T½ 24-48h Neonatal hypotonia Potent amnestic Shown safe at elective CS Effective co-analgesic early labour but potent prolonged amnestic Accumulates in fetus Neonatal hypotonia Impairs neonatal thermoregulation Neonatal respiratory depression 139

18 Sedative Agents: Phenothiazines Used with opioids to provide sedation and reduce nausea/ vomiting Dopamine D2 antagonists in CNS Examples: promethazine (Phenergan), prochlorperazine (Stemetil) Lipid soluble, rapidly cross placenta Side effects: Hypotension Profound sedation Extrapyramidal effects, restlessness Unknown effects on neonatal neurobehavioural scores 140

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20 Anti-emetics Nausea is triggered both centrally in the brain - the chemoreceptor trigger zone (CTZ) in the medulla, and peripherally - the GI tract Vomiting controlled by the vomiting centre (VC) in the brain which is connected neuronally to CTZ Multiple different drug classes interact with receptors in the CRTZ and VC Some drugs are better for nausea, others for vomiting Some drugs work well both as prophylaxis and treatment, others for only one action Nausea/vomiting during pregnancy, labour/delivery, postpartum is common and distressing 143

21 Nausea/vomiting control Pathophysiology of Nausea and Vomiting Vomiting Centre 5-HT 3 receptors NK1 receptors Dopamine receptors CTZ stimulates VC Pregnancy Labour/Delivery Opioids Increased acidity Delayed gastric emptying Altered GI motility Gastric distention 5-HT 3 receptors Dopamine receptors Chemoreceptor Trigger Zone 5-HT 3 receptors NK1 receptors Dopamine receptors Vagus nerve, afferent fibres 144

22 Rationale Management of N/V Nausea/vomiting treatment and prophylaxis Prochlorperazine Droperidol Haloperidol Antihistamines Anticholinergics Dimenhydrinate Scopalamine 145

23 5HT 3 Antagonists Work both as prophylactic and treatment of vomiting and nausea Class D drug in pregnancy and breastfeeding Very efficacious both during pregnancy and peripartum May also reduce neuraxial opioid-induced pruritus Drug Ondansetron Dolasetron Granisetron Route IV IV IV Dose 4 mg proph. 1-2 mg Rx 12.5 mg 0.1 mg Onset minutes minutes minutes Duration 2 h 12-14h Side Effects Headache, palpitations Headache, dizziness Headache, dizziness 146

24 Dopamine Antagonists Metoclopramide: Both peripheral and central dopamine receptor activity Long-standing, considered safe for fetus/neonate Limited efficacy in preventing nausea/vomiting peripartum other than delayed gastric emptying secondary to parenteral opioids Used as pro-kinetic agent by anesthesia prior to CS Droperidol A butyrophenone same drug class as Haldol Extremely efficacious prophylactic and treatment for nausea and vomiting Very cheap Not an approved indication Not recommended if breastfeeding (no evidence) Haloperidol Likely equally as effective as droperidol for nausea/vomiting 147

25 Dopamine Antagonists Drug Metoclopramide (Maxeran) Droperidol Route IM, IV, PO IV IM, IV Dose 20 mg, 10 mg, mg Haloperidol mg mg/kg IM mg/kg IV Onset 10 min 5 min 5 min Durati on Side Effect s 6 h 4-6 h 4-6h Sedation, extrapyramidal Sedation, restlessness, Black Box warning for arrhythmias Restlessness, sedation 148

26 Corticosteroids Unclear mechanism of action, suspected to block prostaglandin synthesis Prophylactic medication not treatment Only proven efficacious steroid is dexamethasone Prophylactic efficacy when combined with 5HT 3 = 90% Cautions: diabetics, infections, morbid obesity wrt wound healing Drug Route Dose Onset Duration Side Effects Dexamethasone IV 4-8 mg (note chemo dose is 20 mg) 10 min 6 hours Fluid retention, hyperglycemia, steroid psychosis 149

27 Antihistamines and Anticholinergics The tried and true Sedating, dry mouth, questionable efficacy. but safe for fetus/neonate Antihistamines: diphenhydramine, dimenhydrinate (Gravol) Anticholinergics: scopalamine (2 o metabolite nightshade plant) Drug Dimenhydrinate Scopalamine Route IM, IV, PO, PR Transdermal Dose 50 mg, 0.5 mg/kg, mg 1.5 mg patch Onset min, 10 min, 30 min 60 min Duration 3-6 h 72 h Side Effects Sedation, extrapyramidal Note: useful for motion sickness Sedation, dry mouth, blurred vision, agitation, hallucinations, urinary retention 150

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29 Opioid Antagonists Naloxone: Reverse neonatal respiratory depression after maternal opioid administration Complete antagonist, therefore reverses analgesia Short effective half-life: 60 minutes Use in smallest effective dose: RR 4-8: 40 mcg q 2min RR 1-4: 100 mcg q 2min Apneic and unconscious: 400 mcg q 2 min Side effects: sympathetic stimulation, hyperarousal, abrupt reversal of analgesia 152

30 Benzodiazepine Antagonists Flumazenil: A benzodiazepine derivative with high affinity for the receptor but minimal intrinsic activity Competition for receptor occupancy Reversal may therefore be partial or complete Dose: mg q 2-3 minutes to max 1 mg Clinical effect of antagonism: min Re-sedation common if mid/long-acting benzo was given, or infusion May repeat dosing, max 3 mg total Elimination T½: 60 min 153

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32 General Anesthesia Unifying theory for mechanism of general anesthesia remains unknown GABA receptors involved, but more complex Definition general anesthesia (GA): Unconsciousness Analgesia Amnesia Muscle relaxation Neonatal effects of GA easily reversed by breathing and time if GA period < 20 minutes induction: delivery Effects on cord gases no worse than spinal anesthesia 155

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34 Optimizing Analgesia Post Cesarean The issues: Only 38% of women post-cesarean rate their pain at day #2 as less than 6/10 Assisted vaginal birth associated with MORE pain than post CD New mothers need to be able to care for their newborn and have minimal side-effects from necessary analgesia Chronic pain post-cesarean is real and underacknowledged 158

35 What is Multi-modal Analgesia? Combining various analgesic agents in order to: Target the many different receptors and neurotransmitters involved in the perception of pain Minimize the side-effects of each agent What different agents? Opioids: pain Give regularly for Acetaminophen: pain the first 48 h for NSAIDs: pain and inflammation maximum efficacy Local anesthetics: pain and inflammation Anti-emetics: n/v increase pain! Anxiolytics: co-analgesic 159

36 NSAID Use Postpartum Opioid sparing and therefore reduces opioid side effects For post-cesarean analgesia: naproxen, indomethacin, ibuprofen, ketoprofen, tenoxicam, diclofenac, ketorolac: number needed to treat for good effect (NNT) Cox-2 inhibitors: Celecoxib No better than standard NSAID for post-cesarean analgesia Benefit comes from lack of effect on platelets: women with thrombocytopenia (ITP, gestational, preeclampsia) or impaired platelet function (preeclampsia) A sulphonamide: sulfa allergy = contraindication Cautions: asthma, renal dysfunction (preeclampsia) 160

37 Analgesia sparing effects of NSAIDs Angle Anesthesiology 2002 regular dosing for 48h 161

38 Opioids for Post-delivery Pain Morphine Meperidine (Demerol) Hydromorphone (Dilaudid) Oxycodone (Oxycontin, oxycodone, oxycet) Codeine 162

39 Intrathecal opioids: post CS analgesia Dahl Anesthesiology

40 Epidural and intrathecal morphine doses 164

41 Neuraxial vs Systemic analgesia post cesarean 165

42 Transfer to Breastmilk? Drug Relative dose to Neonate Clinical Significance? Ibuprofen 0.6 safe Ketorolac Very low breast milk levels Acetaminophen 2 Safe? Glucoronide conjugation Morphine 1-6 Safe but sedation Meperidine 1-3 Normeperidine day 3-4 = neurobehavioural effects 166

43 FDA Drug Classification in Pregnancy Category A B C D Interpretation Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities to the fetus in any trimester of pregnancy. Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women. OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. Animal studies have shown an adverse effect and there are no adequate and wellcontrolled studies in pregnant women. OR No animal studies have been conducted and there are no adequate and wellcontrolled studies in pregnant women. Adequate well-controlled or observational studies in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective. X Adequate well-controlled or observational studies in animals or pregnant women have demonstrated positive evidence of fetal abnormalities or risks. The use of the product is contraindicated in women who are or may become pregnant. 167

44 Drug/drug class Pregnancy Category Breastfeeding Opioids B except remifentanil C Compatible, occasional dose except oxycodone: caution Codeine A Compatible Acetaminophen A Compatible Ibuprofen, naproxyn, diclofenac, ketorolac, celecoxib B-C Compatible Tramadol C Occasional dose Midazolam, lorazepam C Compatible with warning sedation Diazepam D Compatible with warning sedation Phenobarbital, pentobarbital D Avoid Promethazine, prochlorperazine C Compatible short term only Ketamine A Avoid: insufficient data Nitrous oxide A Compatible Desflurane, Sevoflurane?? Naloxone B Caution: insufficient data Flumazenil D Avoid 5HT 3 antagonists B Caution: insufficient data Metoclopramide, dimenhydrinate A Compatible Droperidol D Caution: insufficient data Dexamethasone A Compatible Local anesthetics A except ropivacaine B Compatible Clonidine B Caution may impair breastmilk 168

45 Hydromorphone Semi-synthetic opioid created from morphine with small ester substitution 6 times as potent as morphine May have fewer side-effects than morphine No active metabolite Effective post-partum analgesia 169

46 Hydromorphone Routes Dose Onset Peak effect Duration Fetal/neonatal side effects IM, SC, IV, PO 2-5/ / /2-4 mg 15 min/10 min/5 min/30 min 30/30/20-30/60 min 3-4 hours Minimal data, no active metabolite Dust, juice, smack, D, Footballs, dillies 170

47 Oxycodone Semi-synthetic opioid approximately 1.5 times as potent as morphine Oxycodone metabolism releases small amount oxymorphone Only available as oral preparation Oxycontin Oxycocet or Percocet when combined with acetaminophen Highly addictive and one of most abused drugs in Canada 171

48 Oxycodone Routes Dose Onset Peak effect Duration Fetal/neonatal side effects PO mg min min 4-6 hours FDA Pregnancy Class B Not recommended for breastfeeding Oxy 172

49 Codeine Semi-synthetic opioid derived from morphine Active compound is morphine 5% incidence of hyper-metabolizers (CYPD6 mutation) who produce higher ratio of morphine than expected from dosing More hyper-metabolizers in Asian ethnic groups Low potency, high incidence side effects of nausea/vomiting and dizzyness 173

50 Codeine Routes Dose Onset Peak effect Duration Fetal/neonatal side effects PO mg min min 3-4 hours Maternal hypermetabolizers have higher than expected morphine levels: neonatal depression via breastmilk Dice, sparkle, zoom 174

51 LA Infiltration and Nerve Blocks LA infiltration into cesarean incision provides minimal efficacy Placing a continuous infusion subcutaneously is effective mode of post CD analgesia Transversus Abdominus Plane (TAP) block: US guided, placed after incision closure Bupivacaine or ropivacaine (maximum doses) Provides hours of analgesia Not as effective as epidural/intrathecal morphine but fewer side-effects of opioid 175

52 The end is near.. Opioids and local anesthetics are the mainstay of pharmacological options for labour analgesia 176

53 Next point Opioids and local anesthetics are the mainstay of pharmacological options for labour analgesia NSAIDs, acetaminophen and opioids are the mainstay of postpartum analgesia management 177

54 Opioids and local anesthetics are the mainstay of pharmacological options for labour analgesia NSAIDs, acetaminophen and opioids are the mainstay of postpartum analgesia management Lipid solubility, protein binding and pka are major determinants of drug effect and duration when adminstered perineurally (centrally or peripherally) 178

55 Almost there Opioids and local anesthetics are the mainstay of pharmacological options for labour analgesia NSAIDs, acetaminophen and opioids are the mainstay of postpartum analgesia management Lipid solubility, protein binding and pka are major determinants of drug effect and duration when adminstered perineurally (centrally or peripherally) Most newer agents have not been well studied with respect to use in pregnancy/ breastfeeding, however generally are better drugs with fewer side-effects than the tried and true 179

56 In Summary Opioids and local anesthetics are the mainstay of pharmacological options for labour analgesia NSAIDs, acetaminophen and opioids are the mainstay of postpartum analgesia management Lipid solubility, protein binding and pka are major determinants of drug effect and duration when administered perineurally (centrally or peripherally) Most newer agents have not been well studied with respect to use in pregnancy/breastfeeding, however generally are better drugs with fewer side-effects than the tried and true 180