Opioids

1. Opioids

2. Definitions • Opium: Dried latex from the opium poppy PapaverSomniferum • Opioid: Natural or synthetic pharmaceutical which has an affinity to the opioid receptor • Opiate: natural alkaloid product of opium • Morphine, Codeine, Papaverine • Narcotic: traditionally referred to opioids but more of a legal term for drugs of addiction/abuse

3. Background Opium used by humans since the stone age Opos: Greek for “juice” Mentioned in many ancient texts for various medicinal uses Beneficial (analgesia, hypnotic) and harmful (resp depression, addiction) well known for centuries

4. Brief Opioid History Opium poppies sprung from the tears of Aphrodite when she mourned for her beloved Adonis.

5. Brief Opioid History • Opium is obtained from the exudate of seed pods of the poppy Papaver somniferum

6. Brief Opioid History Opioids used for the treatment of pain for thousands of years

7. Brief Opioid History • 3rd century BC- 1st reference of poppy juice (opium) • 1527 -Paracelsus formulated Laudanum • 1806 - Sertuener isolated ‘soporific principle’ in opium (opium alkaloid) • 1817 - isolated alkaloid named morphine • mid 1800’s - medical use of pure alkaloids began to spread, • 1869 - morphine widely used to treat wounded soldiers during the American Civil War • 1939 - meperidine (phenylpiperidine derivative) was the 1st totally synthetic opioid produced • 1960 - fentanyl synthesized (4-anilinopiperidine derivative; derivative of normeperidine) • 1974-1976 - development of more potent opioid sufentanil and then alfentanil • 1991 - first descriptions of remifentanil

8. Mechanism of Action • Opioids produce affects by activating opioid receptors • Opioid receptors highly concentrated in CNS: • Tractussolitarius • Peri-aqueductal gray midbrain • Cerebral cortex • SubstantiaGelantinosa spinal cord • Also found in • Peripheral nerves

9. Opioid receptors • Coupled with inhibitory G-Proteins • Agonism leads to: • Closing voltage sensitive Ca++ channels • Stimulation K+ influx (hyperpolarization) • Reduced cyclic AMP • Reduced neuronal cell excitation and transmission

10. Mechanism of Action Directly inhibit ascending transmission of nociceptive information in spinal cord dorsal horn (SubstantiaGelantinosa) Mechanism of euphoria unclear but thought to involve dopaminergic pathways in nucleus accumbens

11. Opioid Receptors and Effects • MOP (mu) • mu 1: analgesia, physical dependence • mu 2: resp Depression, miosis, euphoria, dependence, reduced GI motility • mu 3: vasodilation • KOP (kappa) • analgesia, sedation, miosis, dysphoria • DOP (delta) • analgesia, antidepressant, convulsant, dependence • NOP (nociceptan) • anxiety, depression, tolerance

12. Opioid Effects - CNS • Analgesia • Best for visceral pain • Less effective for somatic pain • Poorly effective for neuropathic pain • Sedation • Mental cloudiness • Can induce sleep, possibly because of relief of pain • Not amnestic

13. Opioid Effects - CNS • Euphoria and Dysphoria • In absence of pain may cause dysphoria • Hallucination • More common with kappa agonists • Tolerance and Dependence • May be due to down regulation of receptors • Withdrawal phenomenon: • Restlessness, irritability, salivation, N/V, diarrhea, muscle cramps, sweating • Not fatal but may be dangerous for cardiac patients due to sympathetic stress

14. Opioid Effects - CNS • Mild decreases in Cerebral Metabolic Rate • Mild decrease in ICP • Little or no effect on Cerebral Blood Flow • Muscle Rigidity • More common with high dose / potent opioids • Prevented / attenuated with muscle relaxants

15. Opioid Effects - Cardiovascular Less effects on CVS than other anesthetic drugs More stable at high doses Mild bradycardia Peripheral vasodilation due to histamine release Decrease pre-load Used at high doses in “cardiac anesthesia”

16. Opioid Effects - Respiratory Respiratory Depression (mu receptor) Resp. rate decreases more than Tidal Volume Decreased brainstem sensitivity to CO2 Exacerbated with addition of other anesthestics Suppression of cough reflex Blunt response to intubation

17. Opioid Effects – GI tract • Stimulation of Chemoreceptor trigger zone • Nausea and Vomiting • Use of opioids as risk for Post-op N/V • Increases pressure in biliary tract (exception: meperidine) • Decreased GI tract motility • Constipation

18. Opioid Effects - Other • Endocrine: • Blunt stress response (decrease cortisol, ACTH) • Ocular: • Miosis • Obstetric • All opioids cross the placenta • Chronic use by mother can result in neonatal withdrawal • No known teratogenic effects

19. Balanced Anesthesia • Balance of agents and techniques to produce different components of anesthesia • Analgesia • Amnesia • Muscle Relaxation • Abolition of Autonomic responses • Homeostasis

20. Balanced Anesthesia • Use of Opioids in a balanced anesthetic: • Reduces post-op pain • Reduces post-op anxiety • Decrease autonomic and somatic responses • Hemodynamic stability • Decrease requirements for volatile agents • Decrease requirements for IV anesthetics (propofol)

21. Pharmacokinetics Opioids are weak bases In plasma they dissociate into ionized and unionized fractions depending on pKa Unionized fracture is more freely diffusable Poorly absorbed from acidic stomach (ionized +++) Readily absorbed from small intestine

22. Pharmacokinetics Lipid solubility Protein binding First pass metabolism pKa and ionized/unionized fraction

23. Metabolism • Mainly metabolized by the Liver • Active and inactive metabolites • Morphine • Meperidine • Kidneys involved in conjugation of Morphine

24. Commonly used Opioids • Pure Agonists • Morphine • Codeine • Hydromorphone • Fentanyl • Meperidine • Remifentanil • Alfentanil • Sufentanil • Methadone • Agonist/Antagonists • Pentazocine • Buprenorphine • Antagonists • Naloxone • Naltrexone

25. Morphine • Gold standard opioid / Natural product • MOP receptors • Usual doses • 0.1-0.2mg/kg IM • 1-5mg IV • Hydrophilic • Slower peak onset, extended duration of action • Long duration of action intrathecal/epidural 12-24hrs • Peak onset • IM : 30-60 mins • IV : 10 minutes • Use caution in renal impairment as Morphine-6-Glucuronide accumulates

26. Codeine • Natural opioid • Is a pro-drug, requires metabolism to morphine • Commonly used PO but can be given IM • Unpredictable conversion • 1% over metabolize • 10% under metabolize • This has resulted in deaths • Certain drugs affect enzymatic conversion • Decrease: paroxetine, fluoxetine, bupropion benadryl. • Increase: dexamethasone, rifampacin • Not commonly used in Anesthesia, falling out of favour in pain management

28. Fentanyl • Synthetic, 100x more potent than morphine • IV, IM, transbuccal, transdermal, neuraxial • Peak onset 2-3 minutes IV • Used as induction agent 2-3mcg/kg • IV Boluses 0.5-2 mcg/kg • Spinal 10-25 mcg Epidural 50-100 mcg • Highly lipid soluble / large Vd • Short duration after bolus due to redistribution • Long context sensitive half-time with infusion • Improves onset and quality of block in Spinal and Epidural

29. Hydromorphone (Dilaudid) Semi-synthetic mu agonist 5X as potent as morphine PO, IV, IM, SC, Intrathecal, Epidural More lipid soluble than morphine More water soluble than fentanyl Safer in renal impairment

30. Meperidine (Demerol - Pethidine) • First synthetic opioid, approx 1/5 potency of morphine • Mu and kappa action • Local anesthetic properties • Can be used as a single agent for spinal anesthesia • Unique properties • Decrease spasm in sphincter of oddi • Blocks sodium channels (local anesthetic action) • Results in tachycardia due to muscarinic blockade • Useful to stop shivering response • Downsides: • Metabolites have a long half-life and can cause seizures and accumulate in renal failure • Less commonly used now than in the past

31. Remifentanil • Ultra-short acting, synthetic, highly potent opioid • 200X potent than morphine • Independently metabolized by Plasma esterases due to ester linkage • Useful as an infusion when deep opioid effects required but rapid recovery desired • Used for sedation, GA, TIVA • Usual dose 0.025-1.0 mcg/kg/min • Context sensitive half-time 6 minutes • Bradycardia, hypotension, muscle rigidity more common • Can be used as a co-induction agent “Rem-tubation” • Can result in opioid induced hyperalgesia • No residual effects thus need another opioid post-op

32. Pentazocine • Partial antagonist/agonist • Approx ¼ potency of morphine • IM, SC (less often) IV and PO • Mostly action on kappa receptors • More likely to cause nausea, bizarre dreams • Less respiratory depression • May provoke withdrawal in opioid dependent patients • Less effective for severe pain

33. Naloxone • Pure antagonist at all opioid receptors • Reverses respiratory depression • Resuscitation doses 0.2-.0.4mg • In peri-operative patient these doses may result in severe pain crisis • Small titration doses 0.04-0.08mg • Effective antagonism 30 minutes • May need re-dosing for longer acting drugs

34. Opioids in the OR • Important part of a balanced anesthetic • Decrease MAC • Patient comfort • Blunt stress response – better outcomes • Stable Hemodynamics • The trick is to have an appropriate levels to correspond to the varying stimulation levels of the surgery • Need to anticipate pain control post-op • Want patient to “wake up” comfortably but also want him to “wake up” in a timely manner

35. Opioids in the OR • Opioids have many downsides • Constipation • Delay bowel recovery • Nausea & vomiting • Hallucination • Co-analgesics and regional anesthetic techniques spare their use

36. Opioids in the OR • Often given at induction for intubation • PRN Bolus therapy • Need to anticipate stimulating parts of surgery and “top up” as required • Keep in mind peak onset • Morphine 10 minutes • Fentanyl 2-3 minutes • Background infusions useful • Fentanyl, sufentanil, hydromorphone, morphine

37. Opioids in the OR Unreliable as a single agent Not amnestic Used in conjunction with other agents Dose dependent decrease in MAC for volatile agents Blunt stress/sympathetic responses to pain and intubation

38. Opioids in the OR • Can be given a loading dose with intermittent boluses • Continuous infusion • Pay attention to Context sensitive half-time • Post-op analgesia • Part of a “Balanced Anesthetic” • Smooth out extubation

39. Context Sensitive Half-time • Time for blood levels to decrease by half after a continuous infusion is discontinued • “Context” is the duration of the infusion • Very high for drugs with a large Vddue to accumulation and redistribution • Fentanyl, Sodium-thiopental

41. Opioids in Acute Pain • Main ingredient in multi-modal analgesia • Traditional approach of IM/SC boluses less effective than IV PCA • Avoid peaks/troughs

42. What is the “Best Way” to manage acute post-operative/trauma pain? Effective Analgesic Modalities Patient Safety FIRST, DO NO HARM Therefore, the “best way” is a BALANCE

43. KEY POINTS • “Emphasis is placed on the utilization of a multimodal analgesic approach to maximize analgesia while minimizing side-effects.” • Transduction • Transmission • Modulation • Perception • There is as of yet no single silver bullet!!

44. Acute Pain Management Modalities • Cyclo-oxygenase inhibitors • Non-specific COX inhibitors(classical NSAIDs) • Selective COX-2 inhibitors, the “coxibs” • Acetaminophen is probably COX-3 • Opioids • Local Anesthetics • NMDA antagonists • Ketamine, dextromethorphan

45. Analgesia with Opioids alone Side-effects Analgesia The harder we “push” with single mode analgesia, the greater the degree of side-effects

46. Multi-modal Analgesia Side-effects Analgesia “With the multimodal analgesic approach there is additive or even synergistic analgesia, while the side-effects profiles are different and of small degree.”

47. The rationale for COX-Inhibitors in acute pain management • The problem with the “Little Pain – Little Gun, Big Pain – Big Gun Approach” • With opioids, analgesic efficacy is limited by side-effects • “Optimal” analgesia is often difficult to titrate • >10 – fold variability in opioid dose:response for analgesia in opioid naïve patients! • factors add to the difficulty • Opioid tolerance, anxiety, obstructive sleep apnea, sleep deprivation, concomitantly administered sedative drugs

48. The rationale for COX-Inhibitors in acute pain management • The problem with the “Little Pain – Little Gun, Big Pain – Big Gun Approach” • Patient Safety!! If the “Big Gun” is failing due to dose limiting sedation/respiratory depression, the addition at that time of the “Little Gun” may kill the patient.

49. Opioids Pharmacokinetic + Pharmacodynamic patient to patient variability results in1000 % variability in opioid dose requirements Concept # 1 • opioid dosage must be individualized • therefore, if parenteral therapy indicated, IV PCA much better suited to individual patient needs than IM/SC

50. Patient Controlled Analgesia with Intravenous Opioids • IV PCA: • morphine • golden standard, pruritus a common problem • meperidine • a little faster onset than morphine • normeperidine a toxic metabolite is a problem for patients with decreased renal function or using large dosages for more than a few days • hydromorphone • less confusion in elderly patients?