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  • 1. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 1 |mic-08-13 Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials Image Source: http://www.cnsforum.com/educationalresources/imagebank//default.aspx Opioid Drugs and Opioid receptors e-Notes| From IVMS| Marc Imhotep Cray, M.D. A. Definitions 1. Opioids are drugs with morphine-like activity that produce analgesia (i.e., reduce pain) without the loss of consciousness and can induce tolerance and physical dependence. Opioids are also referred to as narcotic analgesics. 2. Opiates are drugs derived from opium (e.g., morphine, heroin), a powdered, dried exudate of the fruit capsule (poppy) of the plant Papaver somniferum. Opium alkaloids (e.g., thebaine) are used to make semisynthetic opioids. Other opioids are prepared synthetically (e.g., methadone).
  • 2. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 2 |mic-08-13 3. Opiopeptins (endogenous opioid peptides) are natural substances of the body that have opioid-like activity. a. Opiopeptins are localized in discrete areas of the CNS and in a number of peripheral tissues including the GI tract, kidney, and biliary tract. b. Opiopeptins are derived from distinct polypeptide precursors. (1) Preproopiomelanocortin contains b-endorphin (also adrenocorticotropic hormone [ACTH] and melanocyte-stimulating hormone). (2) Preproenkephalin contains the pentapeptides met-enkephalin and leu-enkephalin. (3) Preprodynorphin contains dynorphins A and B and neoendorphins a and b. B. Mechanism of action 1. Opioids such as morphine are believed to mimic the effects of opiopeptins by interaction with one or more several distinct receptors (l, j, d). Each opioid receptor has distinct subtypes (e.g., l1, l2). Opioids with mixed agonist–antagonist properties may act as agonists at one opioid receptor and antagonists at another (e.g., pentazocine) or as partial agonists (e.g., buprenorphine). a. Interaction with l-receptors contributes to supraspinal and spinal analgesia, respiratory depression, sedation, euphoria, decreased GI transit, and physical dependence. b. Interaction with j-receptors contributes to supraspinal and spinal analgesia, sedation, and miosis. c. The significance of interaction with d-receptors is unclear, but it may contribute to analgesia. d. b-Endorphins, the enkephalins, and dynorphins have their highest affinity for, respectively,l–, d–, and j– receptors. 2. Opioids produce analgesia and their other actions by mechanisms that are not completely understood. a. All opioids activate inhibitory guanine nucleotide binding proteins (Gi). b. Opioids inhibit adenylyl cyclase activity, resulting in a reduction in intracellular cAMP and decreased protein phosphorylation.
  • 3. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 3 |mic-08-13 c. Opioids promote the opening of potassium channels to increase potassium conductance, which hyperpolarizes and inhibits the activity of postjunctional cells. d. Opioids close voltage-dependent calcium channels on prejunctional nerve terminals to inhibit release of neurotransmitters (e.g., the release of glutamate and the release of substance P in the spinal cord). e. Opioids raise the threshold to pain by interrupting pain transmission through ascending pathways (substantia gelatinosa in the dorsal horn of the spinal cord, ventral caudal thalamus) and activating the descending modulatory pathways (periaqueductal gray area in the midbrain, rostral ventral medulla) in the CNS. f. Opioids also raise the threshold to pain by action on peripheral sensory neurons. g. Opioids decrease emotional reactivity to pain through actions in the limbic areas of the CNS. C. Psychologic dependence and compulsive drug use 1. The euphoria and other pleasurable activities produced by opioid analgesics, particularly when self-administered intravenously, can result in the development of psychologic dependence with compulsive drug use. This development may be reinforced by the development of physical dependence. 2. Although physical dependence is not uncommon when opioids are used for therapeutic purposes, psychologic dependence and compulsive drug use are not. D. Tolerance and physical dependence 1. Tolerance a. Tolerance occurs gradually with repeated administration; a larger opioid dose is necessary to produce the same initial effect. b. Tolerance is due to a direct neuronal effect of opioids in the CNS (i.e., cellular tolerance). c. Tolerance varies in degree. d. Tolerance can be conferred from one opioid agonist to others (cross-tolerance).
  • 4. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 4 |mic-08-13 2. Physical dependence occurs with the development of tolerance to opioids. a. Abstinent withdrawal (1) Abstinent withdrawal is a syndrome revealed with discontinuation of opioid administration. (2) Abstinent withdrawal is characterized by drug-seeking behavior and physical signs of autonomic hyperexcitability that may include ‘‘goose bumps’’ (‘‘going cold turkey’’). Morphine: prototype 1. Pharmacologic properties a. Morphine is usually given parenterally, but it can be given orally or rectally. b. Morphine undergoes extensive first-pass metabolism with glucuronide conjugation (morphine-6-glucuronide may possess analgesic activity). Dosage adjustment of morphine is necessary in patients with hepatic insufficiency. c. Morphine has a plasma half-life (t1/2) of 2–3 hours; its duration of action is 3–6 hours. 2. Therapeutic uses of morphine and other opioids a. Analgesia (1) Morphine is used for analgesia in severe preoperative and postoperative pain, as well as for the pain of terminal illness; it is used to treat the visceral pain of trauma, burns, cancer, acute myocardial infarction (MI), and renal or biliary colic. Higher doses are necessary for intermittent sharp pain. (2) Morphine produces analgesia by increasing the threshold for the sensation of pain and by dissociating the perception of pain from the sensation. There is significant interpatient variability in this latter effect. (3) In addition to analgesia, decreased anxiety, sedation that is marked by drowsiness, inability or decreased ability to concentrate, loss of recent memory, and occasional euphoria are useful additional properties of morphine in frightening disorders, such as MI and terminal illness.
  • 5. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 5 |mic-08-13 b. Diarrhea (1) The antidiarrheal effect of morphine is a pharmacologic extension of its constipating effect (see below). For this reason, morphine is often used after an ileostomy or colostomy. (2) Morphine is an effective treatment for diarrhea at a less-than-analgesic dose. (3) Codeine is popular because of its reduced abuse liability. Diphenoxylate (with atropine to reduce the likelihood of parenteral use) and loperamide are used widely, because at therapeutic doses, their actions are confined primarily to the GI tract and because their insolubility precludes IV use. (4) No significant development of tolerance occurs to the antidiarrheal action of morphine. c. Acute pulmonary edema (1) Morphine relieves the dyspnea (feeling of shortness of breath and the struggle to breathe) associated with acute pulmonary edema secondary to left ventricular failure. (2) This effect may be due to 1) decreased peripheral resistance with a decreased afterload and decreased venous tone with a decreased preload; 2) decreased anxiety of the patient; and/or 3) depression of the respiratory center and the CNS response to hypoxic drive. d. Myocardial infarction. Vasodilation and the subsequent decreased cardiac preload are of additional therapeutic benefit when morphine is used for the pain of MI. Pentazocine and butorphanol increase preload and are contraindicated for the treatment of MI. e. Cough (1) Opioids are used to produce a direct depression of the cough center in the medulla when the cough is not controlled by nonopioids. Codeine, at a subanalgesic dose, is widely used for severe cough. (2) The receptors are unique in that the cough reflex is depressed by both L-isomers and Disomers of opioids (D-isomers are without analgesic action).
  • 6. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 6 |mic-08-13 f. Anesthesia applications (1) Preanesthetic medication or supplement to anesthetic agents during surgery (a) Opioids are used for analgesic and sedative or anxiolytic effects. (b) Fentanyl is often used for its short duration of action relative to morphine. (2) Regional analgesia (epidural or intrathecal administration) (a) Morphine and fentanyl are used to achieve long-lasting analgesia that is mediated through action on the spinal cord. (b) There is a reduced incidence of adverse effects, but delayed respiratory depression, nausea, vomiting, and pruritus often occur. (3) High-dose fentanyl or congeners (or morphine) are used as primary anesthetic in cardiovascular surgery because of their minimal cardiac depression. g. Physical dependence. Opioids (methadone, buprenorphine) are used to mitigate the withdrawal symptoms of physical dependence caused by other opioids, including heroin. 3. Adverse effects and contraindications of morphine and other opioids a. Respiratory depression (1) Respiratory depression is generally not a serious clinical problem except in several special circumstances. (2) Respiratory depression with opioid use is due to the direct inhibition of the respiratory center in the brainstem and to decreased sensitivity of the respiratory center to CO2 with decreased hypoxic drive; it leads to decreased respiratory rate, minute volume, and tidal exchange. (3) Opioids are contraindicated if there is a preexisting decrease in respiratory reserve (e.g., emphysema) or excessive respiratory secretions (e.g., obstructive lung disease). (4) These drugs are contraindicated in patients with head injury. Cerebral vasodilation results from the increased pCO2 caused by respiratory depression and may result in increased cerebral vascular pressure, which may lead to exaggerated respiratory depression and altered brain function. (5) Opioids should be used cautiously during pregnancy because they may prolong labor and cause fetal dependence.
  • 7. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 7 |mic-08-13 (6) Clinical or accidental opioid overdose with respiratory depression may be treated with artificial ventilation; this may be sufficient for the treatment of respiratory depression or coma. Opioid antagonists can be used to reverse respiratory depression. b. Constipation (1) Constipation results from increased tone with decreased coordinated GI motility, increased anal sphincter tone, and inattention to the defecation reflex. (2) This effect is mediated through actions on the GI tract, to inhibit release of acetylcholine, and on the CNS. (3) There is no clinically significant tolerance to this effect. c. Hypotension (1) Opioids inhibit the vasomotor center in the brainstem, causing peripheral vasodilation; they also inhibit compensatory baroreceptor reflexes and increase histamine release. (2) Opioids should be used cautiously in patients in shock or with reduced blood volume. The elderly are particularly susceptible. d. Nausea and vomiting (1) This common effect of opioids is caused by the direct stimulation of the chemoreceptor trigger zone (CTZ) in the area postrema of the medulla, which leads to activation of the vomiting center; there is also a direct vestibular component. (2) This effect is blocked by dopamine-receptor antagonists. (3) This effect is self-limiting because of the subsequent direct inhibition by morphine of the vomiting center. e. Pneumonia is a potential result of a reduced cough reflex when opioids are used for analgesia, particularly when respiration is compromised. f. Sedative activity with drowsiness places ambulatory patients at risk for accidents. A paradoxical dysphoria occasionally develops. g. Pain from biliary or urinary tract spasm (1) This pain is due to the increased muscle tone of smooth muscle in the biliary tract, the sphincter of Oddi, and the ureters and bladder.
  • 8. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 8 |mic-08-13 (2) These spasms may result in a paradoxical increase in pain when opioids are used to alleviate the pain associated with the passing of urinary or biliary stones if the dose is insufficient to induce centrally mediated analgesia. h. Urine retention (1) This effect, more common in the elderly, is due primarily to decreased renal plasma flow. Other contributing factors include increased tone with decreased coordinated contractility of the ureters and bladder, increased urethral sphincter tone, and inattention to the urinary reflex. (2) Catheterization is necessary in some instances. (3) Opioids should be used cautiously in patients with prostatic hypertrophy or urethral stricture. i. Psychologic or physical dependence. The risk for the development of psychologic dependence or physical dependence is not a valid excuse to withhold opioids and thereby provide inadequate relief from pain, particularly in the terminally ill. j. Miosis (1) Opioid stimulation of the Edinger-Westphal nucleus of the oculomotor nerve results in ‘‘pinpoint’’ pupils even in the dark. This effect is mediated by acetylcholine and blocked by atropine. (2) No tolerance develops to this effect. (3) During severe respiratory depression and asphyxia, miosis may revert to mydriasis. 4. Drug interactions a. Drugs that depress the CNS add to or potentiate the respiratory depression caused by opioids (e.g., sedative–hypnotic agents). b. Antipsychotic and antidepressant agents with sedative activity potentiate the sedation produced by opioids. c. In the presence of opioids, particularly meperidine, MAOIs produce severe hyperthermia, seizures, and coma.
  • 9. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 9 |mic-08-13 2. Fentanyl, sufentanil, alfentanil, remifentanil a. Fentanyl and other subtypes are administered parenterally. They have a shorter duration of action than morphine. Remifentanil is rapidly metabolized by blood and tissue esterases. b. Fentanyl is available as a transdermal patch and lozenge on a stick for breakthrough cancer pain. c. Fentanyl is administered as a preanesthetic and intraoperative medication for its analgesic, anxiolytic, and sedative properties. d. Fentanyl (or morphine) is used in high doses as a primary anesthetic for cardiovascular surgery because it produces minimal cardiac depression. e. Fentanyl is used to supplement the analgesia and sedative–hypnotic effects of nitrous oxide and halothane in a ‘‘balanced anesthesia’’ approach. Morphine also is used for this indication. f. Fentanyl is infrequently used in the combination product fentanyl/droperidol (Innovar) to induce neuroleptanalgesia. This combination permits a wakeful state when patient cooperation is needed (intubations, minor surgical procedures, changing burn dressings). g. These drugs may cause severe truncal rigidity when administered by rapid IV at a high dose. 3. Methadone (also levomethadyl acetate) a. Methadone, like morphine, has good analgesic activity. It is administered orally and has a longer duration of action than morphine. b. Methadone is associated with a less severe withdrawal syndrome than morphine; it is often substituted for other opioids as a treatment for physical dependence because it allows a smoother withdrawal with tapered dose reduction. It is also used for maintenance therapy of the heroin-dependent addict. 4. Meperidine a. Meperidine has a shorter duration of action than morphine. b. Meperidine appears to produce less neonatal respiratory depression than morphine and may be preferred in obstetrics.
  • 10. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 10 |mic-08-13 c. High doses may cause CNS excitation (tremors, delirium, hyperreflexia) and seizures due to formation of a metabolite, normeperidine. d. Meperidine causes severe restlessness, excitement, and fever when administered with MAOIs. e. Meperidine use may result in mydriasis and tachycardia due to weak anticholinergic activity. f. Meperidine has no effect on the cough reflex. G. Weak agonists 1. Codeine, oxycodone, and hydrocodone are partial opioid receptor agonists used for moderate pain. a. They are orally effective and undergo less first-pass metabolism than morphine. b. These drugs are usually used in combination with other analgesics such as acetaminophen, aspirin, or ibuprofen (e.g., codeine/acetaminophen = Tylenol with codeine; hydrocodone/ acetaminophen = Vicodin, Lortab; oxycodone/aspirin = Percodan; and oxycodone/acetaminophen = Percocet). c. These drugs are associated with less respiratory depression than morphine and have less dependence liability. Overdose with codeine produces seizures. 2. Propoxyphene a. Propoxyphene is used as an analgesic; however, it has lower efficacy than codeine. It is usually used in combination with aspirin or acetaminophen. b. Propoxyphene has low abuse liability but can produce respiratory depression and dependence. c. Propoxyphene may cause seizures at high doses. H. Mixed agonist–antagonists/Partial agonists 1. Buprenorphine, pentazocine, nalbuphine, and butorphanol a. Buprenorphine is a partial agonist at opioid l-receptors. b. Pentazocine, nalbuphine, and butorphanol are opioid j-receptor agonists with partial agonist or antagonist activity at opioid l-receptors. 2. These drugs are used for moderate pain. 3. Buprenorphine, like methadone, is used for heroin detoxification.
  • 11. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 11 |mic-08-13 4. Severe respiratory depression, although uncommon, is resistant to naloxone reversal. 5. These drugs have less dependence liability than morphine. 6. These drugs, except nalbuphine, can increase cardiac preload and should not be used to treat the pain of MI. 7. These drugs can precipitate withdrawal if administered to patients already receiving strong opioid agonists. 8. Pentazocine occasionally causes dysphoria, hallucinations, and depersonalization and is not commonly used in clinical practice. I. Tramadol 1. In addition to weak opioid l-receptor agonist activity, tramadol also weakly blocks reuptake of serotonin and norepinephrine—effects that appear to account for its analgesic action. 2. It may have special use for neuropathic pain. 3. Tramadol is associated with an increased risk of seizures and is contraindicated in patients with epilepsy. 4. Its actions are only partially reversed by naloxone. 5. Tramadol should not be administered to patients taking MAOIs. J. Opioid antagonists 1. Naloxone and naltrexone (also nalmefene) are competitive inhibitors of the actions of opioids. 2. These drugs will precipitate opioid withdrawal. 3. Naloxone has a relative short duration of action of 1–2 hours. It is used to diagnose opioid dependence and to treat acute opioid overdose. Because of its short duration of action, multiple doses may need to be administered. 4. Naltrexone has duration of action of up to 48 hours. It is approved for use to help decrease craving for alcohol. K. Antidiarrheal agents 1. Diphenoxylate/atropine, difenoxin, and loperamide are taken orally for the symptomatic treatment of diarrhea. 2. Diphenoxylate is only available combined with atropine to minimize parenteral misuse.
  • 12. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 12 |mic-08-13 3. Insolubility of diphenoxylate limits its absorption across the GI tract. Loperamide does not penetrate the brain. 4. These drugs have minimal dependence liability or other centrally mediated opioid-like effects at therapeutic doses. L. Antitussive agents 1. Dextromethorphan, an opioid isomer, is an over-the-counter cough medication that, like codeine, is used for its antitussive activity. However, it has little or no analgesic or addictive properties at therapeutic doses. Some constipation and sedation have been noted. Links:  http://en.wikipedia.org/wiki/Opioid  Opioid Withdrawal Symptoms—Information about Opioid and opiate withdrawal issues  The use of opioids for chronic pain @ The APS  World Health Organization guidelines for the availability and accessibility of controlled substances  Video: Opioid side effects (Vimeo) (YouTube)—A short educational film about the practical management of opioid side effects. Book: Katzung, B. Basic and Clinical Pharmacology. 11th ed. McGraw Hill Medical, 2009 ---------------------------------------------------------------------------------------------------- Opioid receptors Video| From Pharmacology Corner| By Flavio Guzmán, MD. A video on Mu, Delta, Kappa and ORL1 receptors Source: http://pharmacologycorner.com/opioid-receptors/ By Flavio Guzmán, MD This lecture discusses the following topics:  General classification  Cellular actions of opioid receptors  Anatomical distribution and physiologic effects of mu, delta and kappa receptors  Agonists and antagonists
  • 13. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 13 |mic-08-13  ORL-1 receptors Part 1: Classification and cellular actions Provides an introduction to the classification of opioid receptors, it also discusses the cellular effects of opioid receptor activation (presynaptic inhibition of neurotransmitter release) Part 2: Mu, kappa and delta receptors (including agonists and antagonists) Part 2 lists the most relevant agonists and antagonists for the different subtypes of opioid receptor, then effects upon activation (opioid physiology) are reviewed.
  • 14. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 14 |mic-08-13
  • 15. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 15 |mic-08-13 Part 3: ORL1, nociceptin or orphanin FQ receptor Part 3 is an overview on the recently discovered ORL1 receptor.
  • 16. Opioid Drugs and Opioid Receptors e-Notes and Video Tutorials 16 |mic-08-13 PowerPoint presentation If you prefer to review the figures at your own pace you can review the PPT slide by slide: References and further reading Katzung, B. Basic and Clinical Pharmacology. 11th ed. McGraw Hill Medical, 2009 Koneru A, Sreemantula S, Rizwan. Endogenous Opioids: Their Physiological Role and Receptors. Global J. Pharmacol., 3 (3): 149-153, 2009 McDonald J, Lambert DJ. Opioid Receptors. Continuing Education in Anaesthesia, Critical Care & Pain 2005 5:1 Trescot A, Sukdeb D. Opioid Pharmacology. Pain Physician 2008; 11:S133-S153 --------------------------------------------------------------------------------------