1. Chapter 6: Opioid (Narcotic) Analgesics and Antagonists Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

2. 2 Chapter 6 Outline  Opioid (Narcotic) Analgesics and Antagonists  History  Terminology  Classification  Mechanism of action  Pharmacokinetics  Pharmacologic effects  Adverse reactions  Specific opioids  Dental use of opioids

3. 3Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. History  Haveles (p. 65)  Opium is dried juice from unripe seed capsules of the opium poppy  As early as 4000 B.C., many cultures recognized the euphoric effect  In the early 1800s, morphine and codeine were isolated from opium  Until about 1920, patent medicines containing opium were promoted; when these medicines became unlawful, narcotic (opioid) abuse by injection began

4. 4Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Terminology  Haveles (p. 65)  Narcotics is derived from the Greek word that means “stupor”  Opiates refers to drugs derived from substances in the opioid poppy  Opioids include former opiates but also other structurally different agents, their antagonists, and receptors simulated by opioids

5. 5Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Classification  Haveles (pp. 66-67) (Box 6-1; Table 6-1)  They may be classified by their mechanism of action at receptor sites: agonists, mixed opioids, and antagonists  They may also be classified by their chemical structure  Useful when the patient has a history of allergy  They may be classified by their efficacy

6. 6Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Selected Opioid Analgesics by Efficacy  Haveles (p. 66) (Table 6-2)  Strongest  Morphine intramuscularly (IM) 10 mg  methadone (Dolophine) IM 10 mg, orally (PO) 10 mg  meperidine (Demerol) IM 100 mg, PO 50 mg  hydromorphone (Dilaudid) PO 2 mg  Intermediate  oxycodone (in Percodan, Percocet, Tylox, Roxiprin, Roxicet) PO 5 mg  pentazocine (in Talwin NX) PO 50 mg  Weakest  hydrocodone (in Vicodin, Lortab, Lorcet) PO 5 mg  codeine (Tylenol #3, Empirin #3) PO 30 mg  dihydrocodeine (in Synalgos-DC) PO 30 mg  propoxyphene (in Darvocet-N 100) PO 65 (HCl) or 100 (N)

7. 7Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Mechanism of Action  Haveles (p. 67) (Fig. 6-1; Table 6-3)  Opioids bind to receptors in both the central nervous system (CNS) and the spinal cord, producing an altered perception of reaction to pain  Receptors that mediate specific pharmacologic effects and adverse reactions are stimulated by individual opioids  Natural opioid-like substances are in the body, called enkephalins, endorphins, and dynorphins  Have analgesic action and addiction potential cont’d…

8. 8Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Mechanism of Action  Haveles (p. 67) (Fig. 6-1; Table 6-3)  Opioid receptors include mu (μ), kappa (κ), and delta (δ) receptors  Naloxone is an antagonist at the three receptor sites

9. 9Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Pharmacokinetics  Haveles (pp. 66-68) (Table 6-2)  Absorption: most opioids are absorbed well orally; absorption occurs the through lungs and from nasal and oral mucosa  Distribution: variable first-pass metabolism in the liver or intestinal cell wall  Metabolism: major route is conjugation with glucuronic acid in the liver  Excretion: metabolized opioids are excreted by glomerular filtration

10. 10Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Pharmacologic Effects  Haveles (p. 68) (Fig. 6-2)  In general, the severity of side effects is proportional to the efficacy (strength)  Analgesia: raises the pain threshold  Sedation and euphoria  Cough suppression: depresses the cough center in the medulla (antitussive)  Gastrointestinal (GI) effects: increased smooth- muscle tone of intestinal tract to decreased propulsive contractions and motility

11. 11Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Reactions  Haveles (pp. 68-70) (Table 6-4)  An extension of pharmacologic effects  Respiratory depression: usually the cause of death with overdose  Nausea and emesis: result of direct stimulation of chemoreceptor trigger zone (CTZ) in the medulla  Constipation: caused by tonic contraction of the GI tract  Myosis: pinpoint pupils  Urinary retention: increased smooth muscle tone in urinary tract  CNS effects: occasional stimulation, exhibited by anxiety, restlessness, or nervousness cont’d…

12. 12Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Reactions  Haveles (p. 69)  Cardiovascular effects: may depress the vasomotor center and stimulate the vagus nerve  With high doses, postural hypotension, bradycardia, and syncope may result  Biliary tract constriction: in high doses, may constrict the biliary duct  Histamine release: opioids can stimulate release; itching and urticaria can result  Pregnancy and nursing considerations: not teratogenic; may prolong labor or depress fetal respiration cont’d…

13. 13Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Reactions  Haveles (pp. 69-70)  Addiction: potential is proportional to analgesic strength, tolerance occurs to effects except myosis and constipation  Overdose Major symptom is respiratory depression Major symptom is respiratory depression  Withdrawal: symptoms include yawning, lacrimation, perspiration, rhinorrhea, gooseflesh, irritability, nausea, vomiting, tachycardia, tremors, and chills  Identification of addict: “shoppers”  Treatment: substituting oral form for injectable, going “cold turkey” Methadone maintenance: orally effective, long-acting antagonist Methadone maintenance: orally effective, long-acting antagonist

14. 14Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Allergic Reactions  Haveles (pp. 66, 70-71) (Fig. 6-3; Box 6-1)  Most common type of true allergic reaction includes skin rashes and urticaria  An opioid from a different chemical class should be chosen  Some brands of opioid analgesic combinations are formulated with sodium bisulfate

15. 15Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Drug Interactions  Haveles (pp. 70-71) (Table 6-5)  The respiratory depression produced by opioids is additive with other CNS depressants such as alcohol, sedative- hypnotic agents, promethazine or hydroxyzine  All opioids can interact with monoamine oxidase (MAO) inhibitors  May be an increased effect of meperidine with antipsychotic agents such as chlorpromazine

16. 16Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Specific Opioids  Haveles (pp. 70-74)  Opioid agonists  Mixed opioids  Tramadol

17. 17Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Opioid Agonists  Haveles (pp. 66, 70-72) (Tables 6-2, 6-6)  Morphine: prototype; used parenterally for postoperative pain in hospitalized patients; used orally primarily in treatment of terminal illnesses  Oxycodone: used alone or combined with aspirin (in Percodan) or acetaminophen (in Percocet, Tylox)  Hydrocodone: many combinations with acetaminophen cont’d…

18. 18Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Opioid Agonists  Haveles (pp. 71-73) (Table 6-6)  Codeine: the most commonly used opioid in dentistry, combined with acetaminophen for oral administration: #2 (15 mg), #3 (30 mg), #4 (60 mg)  propoxyphene (Darvon): structurally and chemically similar to methadone, analgesic efficacy has been questioned  meperidine HCl (Demerol): “poor choice for oral use” cont’d…

19. 19Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Opioid Agonists  Haveles (p. 73)  hydromorphone (Dilaudid): an orally effective opioid, reserved for management of severe pain  methadone (Dolophine): used primarily to treat opioid addicts  fentanyl family (Duragesic, Sublimaze), sufentanil (Sufenta), and alfentanil (Alfenta): short-acting parenterally administered agonist opioid analgesics used perioperatively or during general anesthesia

20. 20Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Mixed Opioids  Haveles (pp. 73-74)  Agonist-antagonist opioids  Partial agonists  Opioid antagonists cont’d…

21. 21Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Mixed Opioids  Haveles (p. 73)  Include agonist-antagonist opioid analgesics and the partial agonists  The only mixed opioid for oral use is pentazocine  butorphanol (Stadol), a nasal spray, is also in this group  This group is ripe for research to develop opioids with adequate analgesic potency and fewer side effects

22. 22Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Agonist-antagonist Opioids  Haveles (pp. 73-74)  pentazocine (Talwin): the only agonist- antagonist opioid available in oral form  CNS effects similar to opioid agonists: analgesia, sedation, and respiratory depression  The type of analgesia produced is somewhat different from that produced by agonist opioids  Adverse reactions: sedation, dizziness, nausea, vomiting, and headache cont’d…

23. 23Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Agonist-antagonist Opioids  Pentazocine is available as tablets containing 50 mg of pentazocine and 0.5 mg of naloxone, a pure opioid antagonist (Talwin-NX)  Naloxone is effective parenterally but not orally because it is inactivated  If the contents of the tablet are injected parenterally, the active naloxone will counteract the action of pentazocine  This combination tablet is more difficult to abuse  Parenterally available agonist-antagonists include dezocine (Dalgan), nalbuphine (Nubain), and butorphanol (Stadol) cont’d…

24. 24Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Agonist-antagonist Opioids  Haveles (p. 74)  When originally marketed, these agonist- antagonists were said to have much less addiction potential or even none at all  They were not placed on any narcotic schedule by the Drug Enforcement Administration  Current literature and clinical practice has determined that they do have addiction potential

25. 25Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Partial Agonists  Haveles (p. 74)  The first and only available partial agonist is buprenorphine (Buprenex, Subutex)  In abstinent morphine-dependent patients, it suppresses withdrawal  In stabilized opioid-dependent patients, it precipitates withdrawal

26. 26Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Opioid Antagonists  Haveles (p. 74)  naloxone (Narcan): pure opioid antagonist; active parenterally  The drug of choice for treating agonist or mixed opioid overdoses  It will reverse opioid-induced respiratory depression  nalmefene (Revex): another parenteral opioid antagonist  naltrexone (Trexan): a long-acting, orally effective opioid antagonist  Indicated for maintenance of the opioid free state in detoxified, formerly opioid-dependent patients  Also used in management of alcohol abstinence

27. 27Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. tramadol (Ultram)  Haveles (p. 74) (Table 6-7)  A new, unique analgesic  Has μ: opioid agonist action and inhibits reuptake of norepinephrine and serotonin  Adverse reactions include CNS effects such as dizziness, somnolence, headache, and stimulation  GI tract side effects include nausea, diarrhea, constipation, and vomiting

28. 28Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Dental Use of Opioids  Haveles (pp. 74-75) (Box 6-2)  The advent of nonsteroidal antiinflammatory drugs (NSAIDs) has changed the used of opioids in dental practice  Most dental pain is better managed with use of NSAIDs; in the patient in whom NSAIDs are contraindicated, the dentist has a wide variety of opioids from which to choose  Opioids are only used in rare cases for short periods  Opioids are not indicated for chronic pain