Analgesic drugs

1. Analgesic drugs

2. Opioids
• Endogenous
• Met-enkephalin
• Beta-endorphin
• Dynorphin
• Leu-enkephalin
• Exogenous
• Morphine
• Hydromorphone
• Oxycodone
• Meperidine
• Tramadol
• Fentanyl
• Alfentanil
• Sufentanil
• Remifentanil
• Nalbuphine
• Butorphanol
• Nalorphine

3. Mechanism of action
• Binding of opioid receptors
• G-protein coupled
• Inhibit adenyly cyclase  reduce cAMP
• Excite phospholipase C
• Inhibit Calcium channels, activate potassium channels  membrane
hyperpolarization
• Inhibit presynaptic release of NTs
• Inhibit postsynaptic response of NTs in noceptive neurons
• 4 types – mu, kappa, delta, sigma

4. • Sites
• CNS
• Peripheral
• Effect vary upon duration of exposure  tolerance
• Main action – analgesia
• Other actions – sedation, respiratory depression, etc
• Action depends on binding receptor and binding affinity

5. Pharmacokinetics
• Absorption
• Oral – oxycodone, hydrocodone, codeine, tramadol, morphine,
hydromorphone, methadone
• Oral transmucosal – fentanyl
• IM/ subcute – hydrocordone, morphine, meperidine
• Transdermal – fentanyl
• Intrathecal/ epidural – morphine, fentanyl, hydromorphone

6. Distribution
• Short distribution half-lives (15-20min)
• First-pass uptake by lungs
• Redistribution terminate clinical effects
• Context- sensitive
• Half-lives increases after large doses/ longer duration

7. biotransformation
• Liver CYP system/ conjugation
• High hepatic extraction ratio
• Active metabolites
• Morphine morphine 3-glucuronide, morphine 6-glucuronide
• Hydromophone  hydromorphone 3-glucuronide
• Meperidine  normeperidine (seizures)
• Inactive metabolites
• Fentanyl, sufentanil, alfentanil

8. • Prodrugs
• Codeine –CYP2D6 morphine
• Tramadol –CYP2D6 O-desmethyltramadol
• Hydrocordone –CYP2D6 hydromorphone
• Hydrocordone –CYP3A4 norhydrocordone
• Oxycodone –CYP2D6 less potent active compounds

9. • Remifentanil
• Hydrolysis by nonspecific esterases in RBC and tissue
• Terminal half-life – less than 10 min
• No accumulation, no context-sensitive
• Not affected by hepatic function/ pseudocholine esterase deficiency

10. Excretion
• Kidneys
• Morphine – 5-10% unchanged in urine
• Prolong action in kidney failure

11. CVS effects
• Minimal effect on heart if used ALONE
• Large doses – bradycardia except meperidine (tachycardia)
• Combination with benzo, anesthetics drugs  reduced CO
• Meperidine, hydromorphone, morphine –> histamine release
• Hypertension during opioid based intravenous anesthesia

12. Respiratory
• Respiratory depression, esp RR
• Raise apneic threshold
• Depress hypoxic drive
• Morphine, meperidine – bronchospasm
• Rapid admin, large doses – chest wall rigidity
• Blunt response to intubation

13. Cerebral
• With normocarbia – reduce cerebral blood flow, volume, pressure
• Transient increase in ICP after bolus dose?
• Still more benefit to be used in intubating head injury patients
• Slow eeg with large doses
• Nausea and vomiting due to stimulation of CTZ
• Tolerance, physical dependence
• Opioid-induced hyperalgesia
• Local anesthesia, anti-shivering (meperidine)

14. GI
• Slow GI motility
• Reduce peristalsis
• Constipation
• Treatment - alvimopan, naloxegol, naldemedine
• Biliary colic – opioid induced spasm of sphincter of Oddi
• Treatment – naloxone, glucagon

15. Endocrine
• Reduce neuroendocrine stress response to surgery
• Hormones – catecholamines, cortisol, ADH
• But only at large doses
• Side effects> benefits

16. Other effects
• Cancer recurrence
• Substance abuse

17. Drug interactions
• Meperidine + MAOI = hemodynamic instability, hyperpyrexia, coma,
respiratory arrest death
• Libby Zion case
• CNS depressants + opioids = synergistic CVS, respiratory, sedative
effects
• Alfentanil + erythromycin = prolong half-life of alfentanil

18. • Discuss the use of opioids in anesthesia.
• Do opioids have a place in regional anesthesia? What are the side
effects of neuraxial opioids?
• How do agonists and antagonists differ from opioids such as
morphine? How do epidural opioids work?
• Explain the mechanism of neuraxial opioids.
• Discuss the role of opioids in regional anesthesia.
• What are the pharmacological effects of morphine?

19. Use of opioids in anesthesia
• To provide analgesia and sedation during general anesthesia or MAC
• General anesthesia
• Premed – patient with pain in immediate preop period/ those undergoing RA
• Induction – commonly used adjuvant during induction
• During laryngoscopy and endotracheal intubation – suppression of airway
reflexes, blunting sympathetic responses
• Reduce dose requirements of induction agents
• Opioid with local  reduce pain on injection of propofol

20. • Maintenance
• As adjuvant during inhalation anesthetic technique
• Reduce MAC of inhalational agent
• Analgesic component
• As adjuvant and analgesic for TIVA
• No hypnotic effect by itself
• Emergence
• Small dose opioid during emergence to reduce coughing and bronchospasm

21. • MAC
• To provide analgesia during regional anesthesia block
• Reduce discomfort due to uncomfortable positioning
• Supplement regional block during incision
• Treatment of acute post op pain
• Component of multimodal therapy to treat post op pain
• Parenteral – swift, potent analgesia; IV, IM, SC, transdermal, transmucosal
• Bolus IV – titrate to analgesic requirement, does not maintain steady plasma
levels
• Continuous IV infusion – moderate to severe pain, better pain control, more
side effects, require monitoring

22. • PCA – conscious patients who can cooperate and understand
instructions
• Allow self-dosing, more patient satisfaction
• Regional anesthesia
• Effective, better pain control than systemic opioid, avoids some side effects
• Neuraxial opioids – epidural or intrathecal opoids – major abdominal,
thoracic, orthopedic joint surgeries, urological, gynae, etc.
• Intrathecal – preservative free formulations used, morphine 0.1-0.2mg /
fentanyl 10-20mcg alone or with LA
• Onset and duration depend on drug lipophilicity

23. • Intrathecal morphine up to 24 hrs
• Fentanyl – quicker onset but shorter duration
• Epidural opioids – larger dose than IT
• Combination of epidural LA with opioids- reduce dose and side effects
• Epidural PCEA
• Side effects of neuraxial opioids – respiratory depression, nausea and
vomiting, pruritus, etc.
• Delayed respiratory depression with hydrophilic opioids

24. • Oral opioids – when patients can tolerate oral medications, patients
with moderate to severe pain can be switched to oral from IV opioids
• Dose calculated based on 24hr opioid consumption and appropriate
conversion calculated
• Start minimum and combine with nonopioid drugs

25. Neuraxial opioids
• Epidural
• intrathecal

26. Epidural opioids
• Produce analgesia via 2 mechanisms
• Spinal analgesia – via CSF
• Supraspinal or systemic analgesia

27. Spinal analgesia
• Opioids diffuse through spinal meninges into CSF to produce spinally
mediated analgesia
• Permeability depends on many factors, including lipid solubility
• Once inside CSF, epidural opioids act on spinal opioid receptors in
lamina II of dorsal horn of spinal cord
• Produce antinociception via presynaptic reduction of NT release and
postsynaptic hyperpolarization of dorsal horn neurons

28. • After single dose epidural,
• Lipophilic opioids (eg. Fentanyl) – quicker onset, shorter duration
• Diffuse into surrounding epidural fat and veins, systemic uptake and analgesia
• More rapidly cleared from CSF
• Limit delayed resp depression
• Hydrophilic opioids – after penetration into CSF, stays in CSF to produce spinal
analgesia, spread cephalad to act on brainstem  resp depression
• Dose – fentanyl 50-100mcg, morphine 1-5mg
• Single dose opioid alone or combine with LA

29. • Continuous epidural opioids
• Does not cause motor block or sensory block
• Less hemodynamic compromise compared with LA
• Mechanism – supraspinal/systemic for lipophilic, spinal cord opioid receptors
for hydrophilic ones
• Alone or combine with LA
• As part of PCEA regimen

30. Side effects
• Pruritus, respiratory depression, nausea and vomiting
• Dose dependent
• Rarely cause hypotension, little effect on heart rate and MAP
• Respiratory depression – elderly, underlying pulmonary disease,
decreased respiratory reserve, thoracic surgery, also taking systemic
opioids/sedatives
• Different resp depression profiles between lipophilic and hydrophilic
drugs

31. • Lipophilic drugs – within 2-4 hrs
• Hydrophilic – 6-12 hrs after injection
• Treatment – naloxone (0-1-0.4mg increments) with continuous
infusion
• Nausea and vomiting
• opioid receptors in area postrema and CTZ of medulla
• Treatment – naloxone, ondansetron, droperidol, meto, dexa, etc

32. • Pruritus
• Activation of itch center in medulla
• Not histamine release
• Treatment – naloxone, nalbuphine, droperidol
• Urinary retention
• Activation of spinal opioid receptors  increased detrusor muscle contraction
• Low dose naloxone

33. Intrathecal opioids
• Postop analgesia in OG, ortho, thoroacic, vascular, cardiac, uro,
abdominal surgeries
• Mechanism
• Nociceptive afferents – Ad and C fibres end in laminae I, II, III---substance P
• -->- opioid receptors in laminae I, II and V of dorsal horn of spinal cord pain
• IT opioids into CSF blocks transmission of substance P; mediated by GABA and
glycine
• Lipophilicity determines onset and duration
• Lipophilic - CSF levels fall after injection due to distribution into spinal cord
• Segmental spread, less reaching brain

34. • Hydrophilic
• Slower onset, remain in CSF longer, spread rostral, delayed respiratory
depression
• Exception – IT meperidine – both local anesthetic and opioid properties

35. Advantages of IT opioids
• Smaller doses than IV or epidural
• Limit systemic effects
• Duration of analgesia longer (eg. Morphine) than IV or epidural
• Minimal hemodynamic changes
• No motor block
• No sensory block
• If planned to start anticoagulation, single shot IT morphine – long
duration without epidural catheter
• Sparing effect for LA

36. Side effects of IT opioids
• Dose dependent, incidence similar to other routes
• Respiratory depression
• Minutes to a few hours – lipophilic
• 6-12 hrs – morphine
• Hypoventilation even with normal spo2 and RR
• Sedation
• Supplementary O2 may worsen hypoventilation (remove hypoxic drive)
• Risk increase with systemic opioids and sedatives, old age, opioid-naïve,
obesity, OSA
• Treatment - naloxone

37. • Pruritus
• Most common
• Most noted in facial areas supplied by trigeminal nerve/ genralized
• Cephalad migration of drug ?
• Morphine> fentanyl
• Not histamine mediated
• Low dose IV naloxone/ ondansetron

38. • Nausea and vomiting
• Cephalad migration, interaction in area posterama, may be dose dependant
• Treatment – naloxone
• Urinary retention
• More common than after IV
• Detrusor muscle relaxation
• Nalaxone, catheter
• Sedation
• Generalized muscle rigidity, myoclonic movements, nystagmus,
epileptic seizures (rare)