2. Transmission Modulation Cortex Midbrain Medulla Spinal cord Ventral caudal thalamus Dorsal horn Rostral ventral medulla Periaqueductal gray On the left, sites of action on the pain transmission pathway from the periphery to the higher centers are shown. A: Direct action of opioids on inflamed peripheral tissues. B: Inhibition occurs in the spinal cord. C: Possible site of action in the thalamus. Different thalamic regions project to the somatosensory (SS) or limbic (L) cortex. On the right,actions of opioids on pain-modulating neurons in the midbrain (D) and medulla (E) indirectly control pain transmission pathways. A B C D E SS L Putative sites of action of opioid analgesics

3. CHICAGO TRIBUNE Friday January 26, 2007

4. 3. Opioid Analgesic Drugs The drugs used to alleviate moderate to severe pain are either opiates (derived from the opium poppy) or opiate-like (synthetic drugs). These drugs are together as OPIOIDS. Examples: Opiates: morphine, codeine Opiate-Like: fentanyl, meperidine, methadone See below the structures of some opioid analgesic drugs and derivatives Morphine Pentazocine Meperidine Fentanyl Methadone Sufentanil

5. Morphine analogues

6. 4. Endogenous Opioids: Enkepalins , Endorphins, Dynorphins, Endomorphins Enkepalins: Met-Enkepalin Tyr-Gly-Gly-Phe- Met Leu- Enkepalin Tyr-Gly-Gly-Phe- Leu Endorphins:  -neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro -Lys  -neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro  h-endorphin Tyr-Gly-Gly-Phe- Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val- Thr-leu-Phe-Lys-Asn-Ala-Ile-Ile-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu (31-Residues) Dynorphins: Dynorphin A Tyr-Gly-Gly-Phe-Leu- Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln Dynorphin B Tyr-Gly-Gly-Phe-Leu- Arg-Arg-Gln-Phe-Lys-Val-Val-Thr Endomorphins: Endomorphin 1 Tyr-Pro-Trp-Phe-NH2 Endomorphin 2 Tyr-Pro-Phe- Phe-NH2 Endogenous Opioid peptides are derived from precursor peptides (proopiomelanocortin [POMC]) by protelytic clevage of POMC. POMC present in high level in the CNS (arcuate nuecleus, limbic, brain stem, spinal cord). Enkephalins activate mu (  ) and delta (  ) opioid receptors. Enkephalins have slightly higher affinity for the  than for the  opioid receptor. Endomorphins have very high affinity for the  opioid receptor.

8. OPIOID RECEPTORS Opioids bind to specific receptor molecule that mediates its effects. Several opioid specific receptors have been cloned: Mu (  ), Kappa (  ), and Delta (  ) receptors. These receptors belong to G protein-coupled seven transmembrane receptor family. The amino acid sequences are approximately 65% identical among these receptors, but they have little homology with other G protein-coupled receptors (see below the Figure). Mechanism of Opioid Receptor Function 1.  ,  , and  are functionally coupled to pertussis toxin sensitive heterotrimeric G proteins (Gi) to inhibit adenylyl cyclase activity. 2. Activates receptor-activated K + currents which increase K + efflux (hyperpolarization) reduces voltage-gated Ca 2+ entry. 3. Hyperploarization of membrane potential by K + currents and inhibition of the Ca 2+ influx prevents neurotransmitter release and pain transmission in varying neuronal pathways.

9. Opioid Receptor Expression Pain perception (morphine analgesia) Morphine-control respiration Morphine- depress respiration Nauesea and vomiting Neuroendocrine effects periaqueductal gray, spinal trigeminal nucleus, cuneate and gracile nuclei, thalamus regions, dorsal corn of the spinal cord (DHSC) nucleus of solitract, nucleus ambiguus parabrachial nucleus neurons of the postrema hyphothalamic region, DHSC DHSC  receptor κ receptor  receptor

10. CLASSIFICATION OF OPIOID ANALGESIC DRUGS Strong Agonists: Morphine- 4 hr Meperidine- 2 hr Methadone- long acting (half life 24 hrs) Heroin- 2 hr; 3-fold increase in potency, no acceptable medical value in US Fentanyl- 5 to 45 min, anesthetic Oxycodone- 4 h Moderate Agonists: Propoxyphene Codeine Hydrocodone Mixed Agonist-Antagonists: Pentazocine- agonist on  receptor and weak antagonist at  and  receptor Nalbuphine- similar to Pentazocine but potent anatagonist at  receptor Buprenorphine- lipophilic, about 0.4 mg equivalent to 10 mg morphine, partial  agonist, and antagonist at  receptor Antagonists: Naloxone- it rapidly displaces bound opioids from receptor within 30 sec of IV injection, reverses the respiratory depression and coma due to heroin overdose, competitive antagonist for  ,  , and  receptors with a 10-fold higher affinity for  receptor than for  . Naltrexone- longer duration of action than naloxone, a single oral dose blocks the effects of injected heroin (48 hrs)

11. SELECTIVITY OF OPIOID DRUGS AND PEPTIDES FOR DIFFERENT RECEPTORS Compund    Agonists Morphine +++ + Methadone +++ + Meperidine ++ + + Codeine + + + Etorphine +++ +++ +++ Fentanyl +++ Sufentanil +++ + + Endogenous Peptides Met-enkephalin ++ +++ Leu-enkephalin ++ +++  -Endorphin +++ +++  -Neoendorphin + + +++ Dynorphin A ++ +++ Antagonists Naloxone - - - - - - Naltrexone - - - - - - Mixed aganists/antagonists Pentazocine - + Nalbuphine - - ++ Buprenorphine ++ - - Synthetic opioid peptides DAMGO +++ + CTOP - - - - (+) agonist; (-) antagonist

14. B. GASTROINTESTINAL TRACT Decreases GI motility Increases GI tone Produces constipation (Diphenoxylate-meperidine derivative [Lomotil]) GI spasms can be controlled by atropine (acetyl choline receptor antagonist) Biliary tract spasm. Opioids can exacerbate biliary colic C. CARIOVASCULAR SYSTEM No prominent effects Peripheral vasodilation most prominent effect due to histamine release and decreased adrenergic tone Very high doses may produce bradycardia Orthostatic hypotension D. URINARY TRACT Opioids produce urinary retension Increase tone of urinary sphincter Decrease urine production (increased ADH secretion) E. UTERUS Duration of labor may be prolonged F. BRONCHIAL SMOOTH MUSCLE Therapeutic doses have no effect High doses produce constriction (can aggravate asthma)

16. THERAPEUTIC INDICATIONS PAIN i. Chronic pain (only under some circumstances) Most chronic pain states are not relieved by opioid drugs: central pain trigeminal neuralgia (tic douloureux) causalgia phantom limb pain cancer pain lower back pain These pain states require continuous medication Therapy limited by tolerance and physical dependence Chronic pain arising from terminal illness can be relieved by opioid drugs ii. Acute Pain postoperative pain diagnostic procedures orthopedic manipulations myocardial infarction iii. Preanesthetic medication (fentanyl-derivatives) iv. Dyspnea v. Cough Suppression (codeine, dextromethorphan) vi. Diarrhea and dysentery

17. CONTRAINDICATIONS i. Decreased respiratory reserve emphysema severe obesity asthma ii. Biliary colic iii. Head injury iv. Reduced blood volume v. Hepatic insufficiency vi. Convulsant states

18. ACUTE TOXICITY i . Severe Toxicity Estimates: 30 to 120 mg (oral) of morphine ii. Lethal dose Highly variable: > 120 mg (oral) may be lethal iii. Symptoms Profound coma Depressed respiration (2 to 4/min) Cyanosis Low blood pressure Pinpoint pupils Decreased urine formation Low body temperature Flaccid muscles iv. Treatment Ventilation (do not give 100% oxygen because it can induce apnea) Naloxone (Narcan) will reverse toxic signs Naltrexone has a longer duration of action

19. CHRONIC TOXICITY Tolerance and physical dependence are manifestations of chronic toxicity i. Tolerance Tolerance develops to: Analgesia Euphoria Sedation Lethal dose Nausea Tolerance DOES NOT develop to: Respiratory depression (partial) Miosis Constipation Cross –tolerance develops to other opioids ii. PHYSICAL DEPENDENCE Abnormal physical state in which the drug must be administered to maintain “normal” function. Physical dependence is manifested by “withdrawal symptoms” when administration of the drug is stopped. Physical dependence is a powerful reinforcement for continued drug taking behavior Symptoms: 8 - 12 hrs: lacrimation, rhinorrhea, yawning, sweating 12 – 14 hrs: restless sleep (yen) 48 – 72 hrs: symptoms peak, dialted pupils, anorexia, gooseflesh (cold turkey), restlessness, irritability, tremor, nausea/vomiting, intestinal spasm and diarrhea, muscle spasm 7 – 10 days symptoms end

20. OTHER OPIOIDS Codeine – less potent than morphine mainly used as antitussive Meperidine – less potent than morphine high doses produce excitation and convulsions less smooth muscle spasm and miosis than morphine little antitussive action Diphenoxylate (Lomotil) – meperidine derivative used to treat diarrhea Methadone – long duration of action (24 hr) withdrawal protracted and attenuated used to treat addiction Propoxyphene (Darvon) – mild analgesic action

21. OPIOIDS WITH AGONIST/ANTAGONIST PROPERTIES Pentazocine (Talwin) – less potent than morphine will precipitate withdrawal in dependent individuals may produce dysphoria may be orally Nalbuphine (Nubain) – similar to pentazocine not effective orally Butorphanol (Stadol) - similar to pentazocine not effective orally ANTAGONISTS Naloxone – Eliminated first pass metabolism (half life 60 to 100 min) Readily reverses the coma and respiratory depression of opioid overdose. Rapidly displaces all receptor bound opioid molecules; therefore it is very effective reversing heroin overdose. Competitive antagonist for  ,  , and  ; 10-fold higher affinity for  than for  . This may explain why naloxone readily reverses respiratory depression with only minimal reversal of analgesia that results from agonist stimulation of  receptors in the spinal cord. Naltrexone – longer duration of action (up to 48 hrs)

22. Study Aid- Lecture # 72 Opioid Analgesic Drugs Know about mechanism of nociception (physiology) Dorsal corn of the spinal cord – gate control mechanism Know about classification of opioid analgesic drugs Strong agonists – morphine, meperidine, methadone, heroin, oxycodone, fentanyl Moderate agonists – propoxyphene, hydrocodone, codeine Mixed agonists-antagonists – pentazocine, nalbuphine, buprenorphine Antagonist – naloxone, naltrexone Know about endogenous opioid peptides- Enkepalins, endorphins, dynorphins, endomorphins Know about opioid receptors and the mechanism of action- Mu (  ), Kappa (  ), Delta (  ). All G-protein coupled receptors. Increase K+ efflux (hyperpolarization) and reduce voltage-gated Ca2+ entry. Know about the sites of opioid receptor expression-  - periaqueductal gray, spinal trigeminal nucleus, cuneate and gracile nuclei, thalamus, nucleus of solitract, nucleus ambiguus, parabrachial nucleus, neurons of the postrema, dorsal horn of the spinal cord  - hyphothalamic region  - dorsal horn of the spinal cord Know about the pharmacological actions of opioids: CNS - analgesia, sedation, euphoria, mental clouding, respiratory depression , nausea and vomiting, cough reflex, pupillary constriction (miosis) GI – constipation, biliary tract spasm Know about the contraindications of opioids- Decreased respiratory reserve (emphysema, severe obesity, asthma), biliary colic, head injury, reduced blood volume, hepatic insufficiency, convulsant states Know about tolerance and physical dependence Tolerance develops to – analgesia, euphoria, sedation, lethal dose, nausea Tolerance does not develop to - miosis, constipation, respiratory depression (partial) Physical dependence – treat with methadone (long acting opioid) Know about antitussive and anesthetic usage of opioids Antitussive – codeine, dextromethorphan Anesthetic – fentanyl, sufentanil Know about antagonists Naloxone – readily reverses the coma and respiratory depression of opioid overdose Naltrexone – longer duration of action (up to 48 hrs)

23. 1. All of the following are pharmacological effects of strong narcotic(opioid)-analgesic agonist drugs EXCEPT (A) Activation of the chemoreceptor trigger zone (B) Decreased intestinal peristalsis (C) Decreased arterial Pco2 (D) Suppression of cough reflex (E) Constriction of biliary tract smooth muscle 2. With the continued use of a drug, tolerance develops to all of the following effects of morphine EXCEPT (A) Analgesia (B) Sedation (C) Nausea (D) Euphoria (E) Miosis 3. Death from overdosage of strong opioid-analgesics usually results from (A) Cardiac arrest (B) Respiratory depression (C) Seizures (D) Shock (E) Hypertensive crisis 4. Which ONE of the following will prevent development of an absentinence syndrome in a herion user? (A) Naloxone (B) Propoxyphene (C) Phenobarbital (D) Acetyl salicyclic acid (E) Methadone 5. All of the following statements concerning methadone are correct EXCEPT: (A) It has less potent analgesic activity than that of morphine (B) It has longer duration of action than that of morphine (C) It is effective by oral administration (D) It causes a milder withdrawal syndrome than morphine (E) It has its greatest action on  receptor

24. 6. Which of the following statements about pentazocine is INCORRECT? (A) It is a mixed agonist-antagonist (B) It may be administered orally or parenterally (C) It produces less euphoria than morphine (D) It is often combined with morphine for maximal analgesic effects (E) High doses of pentazocine increase blood pressure 7. Which of the following statements about morphine is INCORRECT? (A) It is used therapeutically to relieve pain caused by severe head injury (B) Its withdrawal symptoms can be relieved by methadone (C) It causes constipation (D) It is most effective by parenteral administration (E) It rapidly enters all body tissues, including the fetus of a pregnant woman 8. Morphine is used therapeutically (A) To suppress the withdrawal syndrome associated with the chronic use of alcohol (B) To induce miosis (C) To treat severe constipation (D) To relieve pain associated with heart attack QUESTIONS 9-12 Match each of the descriptions below with the appropriate drug (A) Loperamide (B) Codeine (C) Naloxone (D) Methadone (E) Dextromethorphan 9. Weak–to-moderate opioid agonist with a higher ratio of oral to parenteral activity than morphine 10. Antitussive with no dependence liability 11. Opioid-receptor anatgonist 12. Strong opioid agonist that has a longer duration of action and produces less intense withdrawal syndrome than morphine

25. 13. Most clinically used opioid analgesics are selective for which type of opioid receptor? A. kappa ( κ ) B. alpha ( α ) C. beta ( β ) D. mu ( μ ) E. delta ( δ ) 14. Codeine has a greater oral bioavailability compared with morphine because of which reason? A. codeine undergoes less first-pass metabolism B. morphine is conjugated more quickly C. morphine directly passes into systemic circulation D. codeine is only available in liquid formulation E. codeine is metabolized more by hepatic enzymes 15. In the case of an opioid overdose, naloxone can be given in repeated doses because of which property of naloxone? A. may have a shorter half-life than the opioid agonist B. is only effective at high cumulative doses C. is needed to stimulate the respiratory center D. is safe only in extremely small doses E. is only a partial opioid agonist Answers: 1. C; 2. E; 3. B; 4. E; 5. A; 6. D; 7. A; 8. D; 9. B; 10. E; 11. C; 12. D; 13. D; 14. A; 15. A