1. OPIOIDS NARCOTIC ANALGESICS Dr. Carl B. Goodman Florida A&M University College of Pharmacy and Pharmaceutical Sciences 308E Science Research Center 599-3128 carl.goodman@famu.edu

2. Pain and Analgesia n Pain- an unpleasant sensory and emotional experience with actual or potential tissue damage or described in terms of such damage. (International Association for the Study of Pain, 1979) n Analgesia- absence of pain

4. OPIOID ANALGESICS Prefers to ”NARCOTICS.” Refers to natural, semi- synthetic and synthetic drugs that relieve pain by binding to opioid receptors in the nervous system. The term ”OPIOID" is preferred to ”OPIATE" because it includes all agonists and antagonists with morphine-like activity, as well as naturally occurring and synthetic opioid peptides.

5. Analgesics OPIATES: are natural occurring compounds obtained from the juices of the opium poppy plant: Phenanthrene Morphine (10%), Codeine (0.5%), Thebaine (0.2%) and Papaverine n OPIOIDS: are natural, semi- synthetic or synthetic compounds that produce morphine-like effects –Heroin from Morphine –Buprenorphine from Thebaine

6. PRIMARY EFFECTS OF OPIOIDS n Mimic Opiopeptins (Endorphins, Enkephalins, and Dynorphins) n Relieve moderate-severe pain and the anxiety that accompanies it (Surgery, Diseases, Severe Injury, and Cancer) n Possibly improved treatments for diseases ranging from Alcoholism to Rheumatoid Arthritis

7. ENDOGENOUS OPIOID PEPTIDE GENES n Proopiomelanocortin - Beta-endorphin - Met-Enkephalin - MSH - ACTH - Beta Lipotropin n Proenkephalin (Tyr-Gly-Gly-Phe) - Methionine enkephalin (Tyr-Gly-Gly-Phe) - Leucine enkephalin n Prodynorphin - Dynorphin A - Dynorphin B - Alpha-neo-endorphin

8. OPIOID RECEPTORS

9. OPIOID PEPTIDE AFFINITY AT THE OPIOID RECEPTORS Beta-endorphin - High affinity for Mu and Delta Receptor - Little Activity for Kappa Met-enkephalin/Leu-enkephalin - High affinity for Delta Receptors - Moderate for Mu - Low for Kappa Dynorphin A - High affinity for Kappa Receptors - Moderate for Mu Endorphin - High affinity for Mu Receptors Adrenorphin and Amidorphin and Opiorphin

10. Opiates (Heroin and Morphine) A)Limbic Region B)Brainstem C)Spinal Cord

11. DISTRIBUTION OF RECEPTORS Brainstem Respiration, Cough, Nausea/Vomiting, Maintenance Blood Pressure, Pupillary Diameter, Control Stomach Secretion Medial Thalamus Mediates deep pain that is poorly localized and emotionally influenced Spinal Cord Receptors in the Substantia Gelatinosa receive sensory input to attenuate painful afferent stimuli Hypothalamus Neuroendocrine secretion and Reproduction (Luteinizing Hormone), Thermoregulation Limbic System The Amygdala contains the greatest concentration of opiate receptors. They do not exert analgesic action, but influence emotional behavior. *Addiction Periphery Receptors found on the Sensory nerve fibers. Like the CNS, they inhibit Ca++ - dependent release of excitatory, proinflammatory substances (Substance P) from the never endings. Immune Cells Response to painful stimuli has not been determined. Involved in one’s ability to respond to stress which affects immune system.

12. ACTION OF AGONISTS AT OPIOID RECEPTORS MOR RECEPTOR n Supraspinal Analgesia n Respiratory Depression n Euphoria/Sedation n Physical Dependence n Decreased GI Motility n Pupil Constriction KOR RECEPTOR n Spinal Analgesia (Dorsal Horn) n Sedation/Dysphoria n Pupil Constriction n Little or no dependence

13. ACTION OF AGONISTS AT OPIOID RECEPTORS DOR RECEPTOR n Analgesia (In the periphery) n Delta agonists show poor analgesia and little addictive potential n May regulate mu receptor activity SIGMA RECEPTOR n Dysphoria n Hallucinations n Psychotomimetic Effects n Pupil Dilation ORPHAN RECEPTOR

14. CELLULAR EFFECTS OF OPIOID LIGANDS n Coupled to Inhibitory G Proteins n Inhibit Adenylate Cyclase n Associated with Ion Channels to increase K + efflux (Hyperpolarization), thus impeding neuronal firing and transmitter release n Reduce Ca ++ Influx

15. OPIOID STRONG AGONISTS Phenanthrenes - Morphine (Roxinal, MS Contin) - Hydromorphone (Dilaudid) - Oxymorphone (Numorphan) - Heroin (Diamorphine, Diacetylmorphine) Phenylheptylamines - Methadone (Dolophine) Phenylpiperidines - Meperidine (Dermerol) - Fentanyl (Sublimaze) - Sufentanil (Sufenta) - Alfentanil (Alfenta) - Remifentanil (Ultiva) Morphinans - Levorphanol (Levo-dromoran)

16. OPIOID MODERATE AGONISTS n Phenanthrenes - Codeine - Oxycodone (Roxicodone) - Dihydrocodeine - Hydrocodone - Tramadol n Phenylheptylamines - Propoxyphene n Phenylpiperidines - Diphenoxylate & Difenoxin - Loperamide *Antidiarrheal Agents: - two tablets followed by one after each diarrheal stool

17. OPIOID AGONISTS and ANTAGONISTS n Phenanthrenes - Nalbuphine - Buprenorphine n Morphinans - Butorphanol (Stadol) n Benzomorphans - Pentazocine (Talwain) - Dezocine (Dalgan) *(Mixed Agonist-Antagonists) Antagonists (DOA) n Naloxone (1-2 hour) n Naltrexone (10 hours) n Nalmefane (8-10 hours) n Alvimopan and Methylnaltrexone Bromide: potent MOR antagonist but poor entry into the CNS

18. OPIOID SIDE EFFECTS n Constipation Is the most common opioid-induced side effect for which tolerance does not develop. Gastric and bowel motility can be slowed as well as secretions from colonic mucosa may be reduced. This results in slow moving, hard stool with difficult defecation. Therefore bowel management should be a preventive approach with regular assessment and aggressive correction to maintain bowel movements (BMs). n Nausea and Vomiting Is more common on beginning or increasing opioid therapy and usually subsides as tolerance develops. Slow, steady titration helps to prevent onset. Dose regimen should be used before drug treatment is initiated. Add an opioid or adjuvant drug so that opioid dose can be decreased. Drug treatment for nausea and vomiting is cause related and can cause sedation. Remember: Monitor sedation closely when antiemetics are needed. Antiemetics should be available if needed. If nausea and vomiting persists then an antiemetic may be needed ATC. Adjustments in diet and activity with relaxation technique may be useful in management of nausea. The antiserotonin drug, ondansetron (Lofran), is a good choice for postoperative nausea and vomiting. It has less sedation and fewer side effects. The IV sedative hypnotic, propofol (Diprivan), can be used to control postoperative symptoms. The drugs traditionally used postoperative may cause unwanted side effects such as increase and/or decrease in blood pressure, tachycardia, bradycardia and increase sensitivity to pain which would increase opioid dose for pain relief.

19. OPIOID SIDE EFFECTS n Pruritus Is rarely accompanied by rash. This side effect is more common when administering opioid by the intraspinal route. Obstetric patients have pruritus more than other patients due to an interaction of estrogen with the opioid at the opioid receptor sites. When the opioid is given by continuous infusion, reduction of the opioid amount is effective and efficient treatment. Addition of or increase in nonopioid and adding a local anesthetic to the epidural opioid solution provides additional or maintains pain relief. Antihistamines may be used. Remember: It is particularly important to monitor sedation when antihistamines are combined with intraspinal analgesics.

20. OPIOID SIDE EFFECTS n Sedation Experienced by most patients, is when opioid therapy begins and significant increases in dosing are made. Remember: Do not to confuse sedation with exhaustion that is relieved by sleep after pain is controlled effectively. Tolerance usually develops. Sedation should be monitored q1h to q2h for 12 to 24 hours and treatment given as needed for the opioid-naïve patient. Caffeine can be added for stimulation. Excessive sedation leads to respiratory depression. Limit other sedating drugs when possible. Decrease opioid dose, if possible, in short-term as well as long-term therapy. An opioid that is given in lower dosage with shorter time interval decreases the peak concentration and is effective in some patients. When dose reduction is not successful, a psychostimulant may be another option. Methylphenidate (Ritalin) or dextroamphetamine is started at 2.5 mg to 5 mg in the morning and midday. Few patients need a dose titration of more than 40 mg. Next a switch of opioid can be made for sedation that persists. When all else fails, a change in route (intraspinal opioid and/or local anethestics) is considered.

21. OPIOID SIDE EFFECTS n Respiratory Depression Is the most feared of the opioid-induced side effects by the healthcare provider. A wider safety margin is provided by the tolerance that develops over time. "Therefore, fear of respiratory depression in patients who have been receiving opioids for more than a week should not pose a barrier to administering adequate opioid doses." n Infants less than six months old, elderly patients who are opioid-naïve and those who have coexisting conditions such as chronic pulmonary disease or major organ failure are higher risk patients for opioid-induced respiratory depression. n Remember: The monitoring for sedation to prevent clinically significant respiratory depression is especially important, because more opioid is needed for opioid-induced respiratory depression than is needed for sedation.