1. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 28 Opioid (Narcotic) Analgesics, Opioid Antagonists, and Nonopioid Centrally Acting Analgesics

2. 2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Analgesics and Opioids  Analgesics are drugs that relieve pain without causing loss of consciousness.  Opioids are the most effective pain relievers available.

3. 3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Opioid Analgesics, Opioid Antagonists, and Nonopioid Centrally Acting Analgesics  Introduction to the opioids  Basic pharmacology of the opioids  Clinical use of opioids  Opioid antagonists  Nonopioid centrally acting analgesics

4. 4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Introduction to the Opioids  Terminology  Endogenous opioid peptides  Opioid receptors  Classification of drugs that act as opioid receptors

5. 5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Terminology  Opioid  A general term defined as any drug, natural or synthetic, that has actions similar to those of morphine  Opiate  Applies only to compounds present in opium

6. 6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Endogenous Opioid Peptides  Three families of peptides  Enkephalins  Endorphins  Dynorphins

7. 7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Opioid Receptors  Three main classes of opioid receptors  Mu receptors  Kappa receptors  Delta receptors

8. Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Classification of Drugs That Act as Opioid Receptors 8

9. 9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Basic Pharmacology of the Opioids  Strong opioid agonists  Morphine  Other strong opioid agonists  Moderate to strong opioid agonists  Agonist-antagonist opioids

10. 10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Source  Seedpod of the poppy plant  Overview of pharmacologic actions  Receptors involved  Pain relief  Drowsiness  Mental clouding  Anxiety reduction  Sense of well-being

11. 11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Therapeutic use: relief of pain  Mechanism of analgesic action  Moderate to severe pain  Constant dull pain vs. sharp intermittent pain  Preoperative treatment of anxiety

12. 12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Adverse effects  Respiratory depression Infants and the elderly are especially sensitive Infants and the elderly are especially sensitive Onset: Onset:  IV 7 min; IM 30 min; subQ up to 90 min, may persist 4–5 hr  Spinal injection—response may be delayed by hours Tolerance to respiratory depression can develop Tolerance to respiratory depression can develop Increased depression with concurrent use of other drugs that have CNS depressant actions (eg, alcohol, barbiturates, benzodiazepines) Increased depression with concurrent use of other drugs that have CNS depressant actions (eg, alcohol, barbiturates, benzodiazepines) Can compromise patients with impaired pulmonary function Can compromise patients with impaired pulmonary function  Asthma, emphysema, kyphoscoliosis, chronic cor pulmonale, bariatric

13. 13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Adverse effects (cont’d)  Constipation  Orthostatic hypotension  Cough suppression  Biliary colic  Emesis  Urinary retention  Euphoria/dysphoria  Sedation

14. 14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Adverse effects (cont’d)  Miosis  Neurotoxicity  Intracranial pressure (ICP)  Birth defects  Adverse effects from prolonged use

15. 15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Pharmacokinetics  Administered by several routes: PO, IM, IV, subQ, epidural, and intrathecal  Not very lipid-soluble  Does not cross blood-brain barrier easily  Only small fraction of each dose reaches site of analgesic action

16. 16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Tolerance and physical dependence  Tolerance Increased doses needed to obtain same response Increased doses needed to obtain same response Develops with analgesia, euphoria, sedation, respiratory depression Develops with analgesia, euphoria, sedation, respiratory depression Cross-tolerance to other opioid agonists Cross-tolerance to other opioid agonists No tolerance to miosis or constipation develops No tolerance to miosis or constipation develops

17. 17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Tolerance and physical dependence  Physical dependence Abstinence syndrome with abrupt discontinuation Abstinence syndrome with abrupt discontinuation About 10 hours after last dose: About 10 hours after last dose:  Initial reaction (yawning, rhinorrhea, sweating) Progresses to: Progresses to:  Violent sneezing, weakness, nausea, vomiting, diarrhea, abdominal cramps, bone and muscle pain, muscle spasm, kicking movements Lasts 7–10 days if untreated Lasts 7–10 days if untreated Withdrawal unpleasant but not lethal, as is possible with CNS depressants Withdrawal unpleasant but not lethal, as is possible with CNS depressants

18. 18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Abuse liability  Precautions  Decreased respiratory reserve  Pregnancy  Labor and delivery  Head injury  Other precautions

19. 19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Drug interactions  CNS depressants  Anticholinergic drugs  Hypotensive drugs  Monoamine oxidase inhibitors  Agonist-antagonist opioids  Opioid antagonists  Other interactions

20. 20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Toxicity  Clinical manifestations Classic triad Classic triad  Coma  Respiratory depression  Pinpoint pupils  Treatment Ventilatory support Ventilatory support Antagonist: naloxone (Narcan) Antagonist: naloxone (Narcan)  General guidelines Monitor full vitals before giving Monitor full vitals before giving Give on a fixed schedule Give on a fixed schedule

21. 21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Morphine  Preparations, dosage, and administration  General guidelines on dosage and administration Preparations Preparations Morphine/Naltrexone (Embeda): designed to discourage morphine abuse Morphine/Naltrexone (Embeda): designed to discourage morphine abuse Dosage and routes of administration Dosage and routes of administration  Oral  Intramuscular and subcutaneous  Intravenous  Epidural and intrathecal  Extended-release liposomal formulation (DepoDur)

22. 22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 28 – 1. Structural similarity between morphine and met-enkephalin.

23. 23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Strong Opioid Agonists  Fentanyl (Sublimaze, Duragesic, Abstral, Actiq, Fentora, Onsolis)  100 times the potency of morphine  Five formulations in three routes Parenteral (Sublimaze) Parenteral (Sublimaze)  Surgical anesthesia Transdermal (Duragesic) Transdermal (Duragesic)  Patch—heat acceleration  Iontophoretic system—needle-free Transmucosal Transmucosal  Lozenge on a stick (Actiq)  Buccal film (Onsolis)  Buccal tablets (Fentora)  Sublingual tablets (Abstral)

24. 24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Strong Opioid Agonists  Alfentanil and sufentanil  Remifentanil  Meperidine  Short half-life  Interacts adversely with several other drugs  Toxic metabolite accumulation  Methadone  Treatment for pain and opioid addicts

25. 25Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Strong Opioid Agonists  Heroin  Used legally in Europe to relieve pain  High abuse liability  Not more effective than other opioids  See Figure 28-2  Hydromorphone, oxymorphone, and levorphanol  Basic pharmacology  Preparations, dosage, and administration

26. 26Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 28 – 2. Biotransformation of heroin into morphine.

27. 27Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Moderate to Strong Opioid Agonists  Similar to morphine in most respects  Produce analgesia, sedation, euphoria  Can cause: Respiratory depression, constipation, urinary retention, cough suppression, and miosis Respiratory depression, constipation, urinary retention, cough suppression, and miosis  Can be reversed with naloxone  Different from morphine  Produce less analgesia and respiratory depression than morphine  Somewhat lower potential for abuse

28. 28Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Moderate to Strong Opioid Agonists  Codeine  Actions and uses 10% converts to morphine in liver 10% converts to morphine in liver Pain and cough suppression Pain and cough suppression  Preparations, dosage, and administration Usually oral (formulated alone or with aspirin or acetaminophen) Usually oral (formulated alone or with aspirin or acetaminophen) 30 mg produces same effect as 325 mg acetaminophen 30 mg produces same effect as 325 mg acetaminophen

29. 29Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Moderate to Strong Opioid Agonists  Oxycodone  Analgesic actions equivalent to those of codeine  Long-acting analgesic Immediate-release Immediate-release Controlled-release (OxyContin) Controlled-release (OxyContin)  Abuse: crushes and snorts or injects medication  2010 OP formulation much harder to crush and does not dissolve into an injectable solution to decrease risk of abuse

30. 30Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Moderate to Strong Opioid Agonists  Hydrocodone  Most widely prescribed drug in the United States  Combined with aspirin, acetaminophen, or ibuprofen  Tapentadol  Analgesic effects equivalent to oxycodone  Causes less constipation than traditional medications  Propoxyphene  Analgesic effect equal to that of aspirin  Combined with aspirin or acetaminophen  Propoxyphene products, such as Darvon and Darvocet, have been withdrawn owing to limited efficacy and the risk of potentially fatal dysrhythmias

31. 31Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Agonist-Antagonist Opioids  Pentazocine  Actions and uses  Preparations, dosage, and administration  Nalbuphine  Butorphanol  Buprenorphine  7-day patch: Butrans  Sublingual film: Suboxone

32. 32Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clinical Use of Opioids  Pain assessment  Essential component of management  Based on patient’s description  Evaluate: Pain location, characteristics, and duration; things that improve/worsen pain Pain location, characteristics, and duration; things that improve/worsen pain Status before drug and 1 hour after Status before drug and 1 hour after

33. 33Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Dosing Guidelines  Assessment of pain  Pain status should be evaluated before opioid administration and about 1 hour after  Dosage determination  Opioid analgesics must be adjusted to accommodate individual variation  Dosing schedule  As a rule, opioids should be administered on a fixed schedule  Avoiding withdrawal

34. 34Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clinical Use of Opioids  Physical dependence  State in which an abstinence syndrome will occur if the dependence-producing drug is abruptly withdrawn; it is NOT equated with addiction  Abuse  Drug use that is inconsistent with medical or social norms  Addiction  Behavior pattern characterized by continued use of a psychoactive substance despite physical, psychologic, or social harm

35. 35Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clinical Use of Opioids  Balance the need to provide pain relief with the desire to minimize abuse  Minimize fears about:  Physical dependence  Addiction

36. 36Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clinical Use of Opioids  Patient-controlled analgesia  PCA devices  Drug selection and dosage regulations  Comparison of PCA with traditional intramuscular therapy  Patient education

37. 37Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clinical Use of Opioids  Using opioids in specific settings  Postoperative pain  Obstetric analgesia  Myocardial infarction  Head injury  Cancer-related pain  Chronic noncancer pain

38. 38Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 28 – 3. Fluctuation in opioid blood levels seen with three dosing procedures.

39. 39Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. REMS  Risk evaluation and mitigation strategy (REMS)  Developed by the FDA  Designed to reduce opioid-related injuries and deaths

40. 40Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Opioid Antagonists  Drugs that block the effects of opioid agonists  Principal uses:  Treatment of opioid overdose, relief of opioid- induced constipation  Reversal of postoperative opioid effects  Management of opioid addiction

41. 41Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Pure Opioid Antagonists  Naloxone (Narcan)  Other pure opioid antagonists  Methylnaltrexone (Relistor)  Alvimopan (Entereg)  Naltrexone (ReVia, Vivitrol)

42. 42Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Naloxone  Mechanism of action  Competitive antagonist  Pharmacologic effects  Pharmacokinetics

43. 43Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Naloxone  Therapeutic uses  Reversal of opioid overdose Drug of choice with pure opioid agonist overdose Drug of choice with pure opioid agonist overdose Titrated cautiously with physical dependence Titrated cautiously with physical dependence  Reversal of postoperative opioid effects Titrated to achieve adequate ventilation and to maintain pain relief Titrated to achieve adequate ventilation and to maintain pain relief  Reversal of neonatal respiratory depression Opioids given during labor and delivery may cause respiratory depression in neonate Opioids given during labor and delivery may cause respiratory depression in neonate

44. 44Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Naloxone  Preparations, dosage, and administration  Preparations and routes  Opioid overdose  Postoperative opioid effects  Neonatal respiratory depression

45. 45Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Opioid Antagonists  Methylnaltrexone  Selective opioid antagonist  Treatment of opioid-induced constipation in late- stage disease for patients on constant opioids

46. 46Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Nonopioid Centrally Acting Analgesics  Relieve pain by mechanisms largely or completely unrelated to opioid receptors  Do not cause respiratory depression, physical dependence, or abuse  Not regulated under the Controlled Substances Act

47. 47Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.  Tramadol (Ultram])  Suicide risk  Clonidine (Duraclon)  Ziconotide (Prialt)  Dexmedetomidine (Precedex) Nonopioid Centrally Acting Analgesics

48. 48Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Tramadol  Mechanism of action  Combination of opioid and nonopioid mechanisms  Therapeutic use  Pharmacokinetics  Adverse effects and interactions  Drug interactions  CNS depressants  Abuse liability  Preparations, dosage, and administration  Immediate-release and extended-release

49. 49Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clonidine  Mechanism of pain relief  Alpha 2 -adrenergic agonist  Analgesic use  Used in combination with opioid analgesic  Pharmacokinetics  Adverse effects  Cardiovascular: severe hypotension, rebound hypertension, bradycardia  Contraindications  Preparations, dosage, and administration

50. 50Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Ziconotide  Mechanism of action  Selective antagonist at N-type voltage-sensitive calcium channels on neurons  Blocks calcium channels on primary nociceptive afferent neurons in dorsal horn of the spinal cord  Clinical trials  Three randomized clinical trials

51. 51Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Ziconotide  Pharmacokinetics  Distributed through cerebral spinal fluid (CSF) and then transported to systemic circulation  Adverse effects  CNS and muscle injury  Drug interactions  Formal studies not done  Preparations, dosage, and administration  Intrathecal administration