Opioid Analgesics PDF 2022

Opioid Analgesics by Prof. Mahran. S. Abdel-Rahman Sphinx University Clinical Pharmacy Batch 2022  Analgesics (pain killers) Commonly used pain killers are: 1) Opioids 2) NSAIDs 3) Local anesthetics 1) Some antiepileptics 2) Some antidepressants ...

Opioid Analgesics by Prof. Mahran. S. Abdel-Rahman Sphinx University Clinical Pharmacy Batch 2022  Analgesics (pain killers) Commonly used pain killers are: 1) Opioids 2) NSAIDs 3) Local anesthetics 1) Some antiepileptics 2) Some antidepressants  OpioidsTerminology Opiates: ‫المستحضر األفيوني‬ - Agents derived from NATURAL opium poppy either: Natural alkaloids e.g., morphine, codeine, or Semisynthetic derivatives e.g., heroin. Opioids: ‫أَ ْفيُو ِنيَّاتُ ال َمفْ ُعول‬ – Any substance with morphine-like actions and their effects blocked by antagonist such as naloxone. – Natural, semisynthetic and synthetic compounds (e.g., morphine, heroin , fentanyl, tramadol, etc). Opioid analgesics: - Drugs which relieve pain, however produce drowsiness, change mood and mental clouding. Opiopeptides: – Naturally endogenous ligands acting on opioid receptors e.g., Endorphins, Dynorphins, Enkephalins.  Classification of Opioids According to their action on opioid receptors Pure opioid agonists: – Drugs acting as agonist on opioid receptors and produce morphine-like effects (e.g., Morphine and Fentanyl). a) Morphine and its analogs: e.g., morphine, codeine, tramadol & heroin b) Meperidine and its analogs: e.g., Meperidine, fentanyl, sufentanyl c) Methadone and its analogs: e.g., methadone and propoxyphen Pure opioid antagonists: – Drugs acting as antagonists on opioid receptors and prevent the effects of opioid agonists (e.g., Naloxone & Naltrexone). Mixed agonists/antagonists: – Act as agonists at some opioid receptors and as antagonists at other opioid receptors (e.g., Nalbuphine, Pentazocine & Buprenorphine). Classifications-based on analgesic efficacy. Mechanism of action of opioids -Opioids act by binding to endogenous opioid receptors (Mu: µ, Kappa;  and Delta;  receptors) in the CNS and extra- cerebral tissues. -These receptors are G-protein coupled receptors that act by: a- Inhibition of adenyl cyclase with  in cAMP. b- Opening of potassium channels increasing K+ efflux. c- Blocking of voltage-sensitive Ca++ channels. a- Block of voltage-sensitive Ca++ channels. Opioid receptors are G-protein coupled receptors b- Increases K+ efflux. + c- decrease cAMP Decrease in cAMP  Opioid Receptors μ1: supraspinal analgesia. μ μ2: spinal analgesia, respiratory.depression, sedation, euphoria, miosis and decreased GIT motility (constipation). spinal analgesia, κ dysphoria, Sedation & respiratory depression (less than Mu). analgesia at both spinal and supraspinal δ analgesia.  Endogenous Opiopeptides They are Endogenous peptides interact with opioid receptors so called opiopeptides to cause analgesia and modification of pain sensation. They are very strong analgesics and widely distributed in the CNS and in the GIT. They can’t cross the BBB and if used I.V they are ineffective. They include endorphine, enkephaline, dynorphine & noceciptin.  I- Morphine * Pharmacological actions: Central Nervous System Cardiovascular Effects Gastrointestinal tract Other smooth muscles Metabolism  I- Morphine and its congeners 1. Morphine (prototypical opioid) 2. Codeine 3. Tramadol Collecting resin of opium poppy  1. Morphine Pharmacological actions of morphine 1. CNS effects a) Analgesic b) Sedation, hypnosis and clouding c) Euphoria d) Miosis e) Respiratory depression f) Antitussive. g) Nausea & Vomiting  a) Analgesia & Euphoria Morphine relieve severe types of pain “both visceral and somatic pain” without affecting consciousness. Mechanism of analgesia: The analgesic effect of morphine may be related to: a) Interference with pain perception: by inhibiting pain impulse transfer to the brain (anti-nociceptive effect) b) Euphoriatic action: modify emotional reactions to pain through euphoria. Euphoria: False sensation of well-being especially in presence of pain, anxiety or addiction. This effect may be due to inhibition of inhibitory effect on the locus ceruleus (LC) activity which contains dopaminergic neurons and high conc of opioid receptors (i.e., mediated by increased dopamine).  b) Sedationa, hypnosis and mental clouding Morphine causes sedation, hypnosis and mental clouding (drowsiness, decrease physical activity, decrease ability to concentrate and mental apathy). These effects are due to CNS depression by morphine. c) Respiratory depression Morphine causes depression of all phases of respiratory activity by suppressing respiratory center.  d- Antitussive, e) Miosis & f) Vomiting Antitussive: (non-productive dry cough) – It depresses the cough center – It is the most useful drug in treatment of dry non- productive cough, but it is not used due to its addicting properties. Miosis (Pin-point pupils): (in toxic doses). – Due to activation of occulmotor nucleus in the brain (i.e., of central origin). – The pinpoint pupil is the characteristic of morphine addict or user with little tolerance. Emesis: morphine causes nausea & vomiting by stimulating the CTZ (in the medulla.  2. GIT Effects i. Antimotility & constipating effects: Morphine increases smooth muscles tone of intestine & anal sphincters, decreases motility → Constipation (no tolerance) Decreases gastric emptying & all GI secretions (saliva, gastric, intestinal and pancreatic). ii. Biliary spasm: Morphine increases pressure in the biliary tract by producing spasm in the sphincter of Oddi & increases biliary colics. This spasmogenic effect could be overcome by Concurrent use of atropine or nitrates as nitroglycerin (more acceptable than atropine).  3. Effects on other smooth muscles Ureter and urinary bladder: – Urinary retention due to  tone of urinary sphincter. Postoperative urinary retention is frequently encountered. Treated by catheterization. Bronchial muscles: – In asthmatics, morphine is contraindicated because of bronchoconstrictor effect due to histamine release.  4. Effect of Morphine on CVS Morphine → VD → Orthostatic hypotension (fainted on standing up). Morphine → VD → relieve pulmonary veins congestion. 5. Neuroendocrine Effect of Morphine – ADH release → Urinary retention. – Block the release of testosterone → Impotence – Block the release of gonadotrophines from pituitary → hypogonadism & infertility. – Release of ACTH → Hyperglycemia  6. Effect of morphine on histamine release Histamine release is stimulated by morphine  – Hypotension. – Itching – Bronchospasm (so, morphine should never be given to asthmatics).  I- Morphine * Pharmacokinetics: Absorption From Oral, Parenteral and rectal Distribution To all including CNS & Placenta Metabolism Excretion  Metabolism of morphine Metabolism: – Glucuronide conjugation in the liver: Morphine 6-glucuronide: is more active as an analgesic than morphine (produces long-lasting effect of morphine with chronic dosing). The half-life of morphine-6-glucuronide is much longer than morphine. Morphine-3-glucuronide: with little or no analgesic activity (no affinity to opioid receptors). – Because of low conjugation capacity in neonates, morphine and its congeners should not be used in the neonatal period and the dose should be reduced in elderly. Excretion: Via Bile and kidneys as conjugated metabolites Metabolic pathways of morphine and codeine Active analgesic Excreted by kidneys No analgesic activity * Therapeutic uses of Morphine 1- Pain killer in severe pain 2- Cardiac asthma with pulmonary edema (LSHF) 3- In preanesthetic medication if there is preoperative pain. 4- Antitussive in dry cough 5- to check severe diarrhea  Therapeutic uses of morphine 1. Analgesic: in severe acute constant pain; – Burns, postoperative pain, fracture pain, pain due to biliary and renal colics (with spasmolytics), acute MI & cancer pain. – Given IV or S.C. BUT! – In shock: repeated SC injections of morphine must be avoided why? because absorption is improved after termination of shock → toxicity. So, it is not recommended to be used SC in shocked patients. – Excessive use postoperatively must be avoided→ urinary retention, respiratory depression, constipation. – In gall stone biliary colics → biliary spasm (worsen pain) # with atropine or nitroglycerin spasmolytics. Q: Why atropine must be given with morphine to patients with biliary colics.  Cont. therapeutic uses of morphine 2. Cardiac asthma (LSHF with pulmonary edema): – Reduces anxiety & fear, reduce both preload and afterload (VD effects) → relieving dyspnoea due to pulmonary oedema. 3. Antitussive: – Morphine is effective in dry non-productive cough. However, non-addicting drug dextromethorphan is preferred to be used for this purpose. 4. To check severe diarrhea: – In the past, crude opium has been used to check severe diarrhea. – Now, non-addicting meperidine analogues are used in severe diarrhea e.g., Loperamide and Diphenoxylate.  Therapeutic uses of morphine cont 5. Preanesthetic medication: Due to sedative, anxiolytic, and analgesic properties. Systemically with local anesthetics (epidural anesthesia) for 48 h duration. Used as supplement with general anesthesia. Caution: respiratory suppression & urinary retention in elderly.  Precautions of Morphine shocked / epileptic Acute abdomen During labour/ patients pregnancy Asthma Precautions & relative contraindications Hepatic or Renal Head Injury Impairement Extreme ages  Precautions and relative contraindications 1. Asthmatic patients why? – Depress respiratory centre. – Depress cough reflex. – Histamine releasing agent (bronchoconstriction) – Dry respiratory secretions 2. During labour: – It is not given to the mother if labor is expected within 4-5 h as it crosses placental barrier causing depression of the respiratory center of newborn and causing asphyxia neonatorum. 3. Head injuries: – Morphine depress respiration →  CO2 retention and subsequent VD→  intracranial pressure (ICP). 4. Old people and infants: More susceptible to respiratory depressant effect of morphine. 5. Acute abdomen: e.g., appendicitis and ectopic pregnancy. – Morphine mask diagnosis and hence rupture may happen.  Precautions and contraindications of morphine use 6. Hypovolumia due to hemorrhage: Hypotensive + hypovolumia + hemorrhage = circulatory collapse. 7. Patients with severe hepatic / renal dysfunctions: – Inadequate metabolism/ excretion → drug accumulation and toxicity. 8. Patients with epilepsy: as morphine may increase the epilepsy. 9. Chronic alcohol users: cross tolerance. 10. Alone in Biliary colic: spasm of Oddi exaggerates pain. 11. SC in shocked patients: to avoid toxicity after circulation improvement.  Acute Toxicity of Morphine Manifestations: Respiratory depression. Postural hypotension. Constipation. Nausea & Vomiting. Urinary retention (with BPH in elderly). Increased intracranial pressure Itching and urticaria * Triad Symptoms of Acute Morphine Poisoning: Coma Normal versus pinpoint pupil Depressed respiration Pin point pupils  Treatments of Acute morphine poisoning In Non- Addict Patients: – I.V. Naloxone (pure opioid antagonist): reverse respiratory depression in magic way. In case of newly born baby, naloxone is injected into umbilical cord if poisoned during delivery. – Oral naltrexone is useful in mild conscious cases. – ABC (airway-Breathing and Circulatory )support. – Gastric lavage & emesis are indicated immediately after poisoning ingestion (patient must be conscious). In Addict Patients: – Naltrexone orally or Naloxone (I.V) very cautiously because may precipitate withdrawal syndrome in dependent subjects and cause undesirable cardiovascular side effects + ABC + Gastric lavage and/or emesis.  Chronic toxicity (ADRs) Due to repeated exposure of morphine (opioids): 1. Morphine Dependence (both physical and psychic): – Definition: compulsory use of drug as a result of habitual control on physiological or psychological properties. The patient become a slave to the drug. – Reinforcement factor: euphoria. – Manifestation: Warm flushing skin - Euphoria Sensation in the lower abdomen described by the addict as similar to sexual orgasm known as rush, kick or thrill. – Tolerance and withdrawal syndrome: are characteristics of opioid dependence – Outcomes of dependence: social problems as divorcing + impotence.  ADRs Cont 2. Morphine Tolerance: – Decrease in response to the drug # by increasing doses – Not develop to all morphine actions. Developed to analgesia, respiratory depression, sedative and euphoria. Not developed to constipation and miosis. 3.Withdrawal syndrome due to: a) Sudden withdrawal of morphine b) The use of antagonist as naloxone Manifestations: opposite to the action of morphine – Autonomic hyperactivity: lacrimation, rhinorrhea, sweating, dilated pupils, hypertension and tachycardia. – Psychological hyper-excitability: anxiety, restlessness, yawning, tremors and insomnia. – Motor hyperactivity: Muscle and joint pain, tremors.  TTT of morphine dependence 1. Gradual morphine withdrawal 2. Methadone orally: Replacement of morphine by another agents with lower abuse potential as methadone orally. – Methadone has a cross dependence with morphine but with low abuse potential. 3. Use of clonidine (2-agonists) to control autonomic hyperactivity. 4. Using of partial opioid agonist: as buprenorphine (SL) (has lower abuse potential, suppress withdrawal symptoms and decrease craving for opioid). 5. Methylnaltrexone: has important role in the management of constipation in patient undergoing chronic opioid therapy or addict patients. Psychotherapy is essential.  Morphine derivatives a) Codeine It is Methyl morphine and acts as weak µ-agonist. Weak Analgesic potency – Of 1/12 of morphine (140 mg codeine is equipotent to 10 mg morphine), – Used in mild pain not responding to NSAIDs. – It is usually combined with aspirin or paracetamol to control pain. Highly effective orally: little first pass metabolic effect. Powerful Antitussive. Lower addiction liability and lower withdrawal effects than morphine. Frequently in the past (1950-1990), codeine was prescribed and dispensed in antitussive and cold preparations (e.g., Tussivan, Paracodeine, and others) using normal non-narcotic prescriptions. However, now it is scheduled drug and used by narcotic prescription.  Morphine derivatives Cont. b) Tramadol. - Synthetic codeine analogue with weak  agonist activity. - It also inhibits the reuptake of norepinephrine and serotonin in the CNS. - Has active metabolite (O-demethylated) -2-4 times more potent than the tramadol and may be responsible for part of the analgesic effect. - Naloxone is partially prevent the analgesic effect of tramadol. - Tramadol is effective in treatment of mild to moderate pain as morphine but less effective in chronic and severe. - It does not depress the respiration or CVS but may cause convulsions. - The abuse and dependence is less than morphine. Morphine derivatives Cont. c) Heroin (diacetylmorphine). It has high addiction potential, so it is not used clinically. The analgesic effect is 2 times as morphine.  II- Meperidine (Pethidine) Disadvantages: – 1/10th in analgesic potency (10 mg morphia = 100 mg pethidine) – Tachycardia (due to antimuscarinic action)- harmful in tachyarrhythmias. – It was believed to provides short-lasting analgesia and has little or no addiction because of its shortened duration; however, this belief proved false. – Not used I.V. (cause severe reaction) and not used S.C. (causes local irritation and tissue induration),BUT Used I.M Advantages: a) Spasmodic action on smooth muscles is much less than morphine BUT may be spasmolytic (so, non-harmful in Gallstone colics). b) Safer in asthmatics than morphine (less histamine release). c) Not produce respiratory depression like morphine. So, preferred opioid analgesic during labour (less neonatal respiratory depression). d) It can be used in treatment of postanesthetic shievering  Side effects of Meperidine 1- Similar to that of morphine (but less constipation and urinary retention). 2- CNS excitation (tremors, hyperreflexia and convulsions) due to the formation of normeperidine metabolite. 3-Physical dependence: is common and withdrawal syndrome has rapid onset and short duration (it disappears within 24 h.) with less autonomic manifestations.  Meperidine derivatives a) Fentanyl, alfentanil, remifentanil & sufentanil Fentanyl: - μ (mu) receptor agonist - Very high potency (100 times or more than morphine). - Used as I.V. anesthetic with droperidol to produce neuroleptanalgesia. - High dose of fentanyl can cause muscle rigidity. - Fentanyl Transdermal Patch (Durogesic; 25, 50, 75, 100 μg) is available for use in cancer pain giving long-lasting analgesic effect (48h). Fentanyl derivatives: - e.g., sufentanil and alfentanil - Used in: a) General anesthesia, b) Acute post-operative analgesia c) Treatment of chronic pain.  Meperidine derivatives b) Diphenoxylate & Loperamide. - Non addicting opioids (in therapeutic dose) used in diarrhea - Diphenoxylate may combined with atropine (Lomotil). - They act by decreasing intestinal motility and secretion. However, - They are contraindicated in acute diarrhea in children (due to the risk of paralytic ileus and respiratory depression) - Also, Contraindicated in amebic and bacillary dysentery (as they increase the ulceration and may cause toxic megacolon).  III- Methadone - μ (mu) agonist. - Methadone is Used in the treatment of morphine addiction –Why? a) More effective orally b) Longer in duration c) Lower potential for addiction and less euphoric effect. d) Tolerance and physical dependence develop slowly. e) Symptoms of withdrawal are milder than morphine. f) Sedative effects are less intense than morphine. g) Use as substitute therapy for opioid dependence (1 mg methadone replace 4 mg morphine). IV- Mixed agonist-antagonist a) Pentazocine - It is agonist on κ-receptor, but weak antagonist (partial agonist) on μ receptor. - It has 1/5 of the analgesic effect of morphine. - It causes tolerance, dependence and respiratory depression but less than morphine. - It is not used in addicts to μ-agonist, as it can precipitate withdrawal syndrome. - In patients with coronary artery disease I.V. pentazocine increases pulmonary artery pressure and cardiac work. - It is used as analgesic in chronic severe pain but due to its cardiac effects, it is not used in patients with CHF or myocardial infarction. IV- Mixed agonist-antagonist b) Butorphanol - It is agonist on κ-receptor, but weak antagonist (partial agonist) on μ receptor. - Unlike pentazocine,it precipitates withdrawal syndrome in methadone addicts but not in morphine addicts. - It is used I.V. or I.M. to control acute pain. IV- Mixed agonist-antagonist c) Nalbuphine. -It is agonist on κ-receptor, but weak antagonist (partial agonist) on μ receptor. -As pentazocine, but does not affect CVS, so can be used as analgesic in cardiac patients. IV- Mixed agonist-antagonist d) Buprenorphine - Its potency is 25-50 times as morphine. - The addiction liability is lower with less withdrawal syndrome than morphine. - It acts as partial agonist on μ-receptors with no action on κ-receptors. - Uses: 1-It can be used as analgesic. 2-It can be used as alternative to methadone for opioid detoxification and as a maintenance treatment for opioid dependence as it can prevent the withdrawal syndrome. V- Pure opioid antagonists Naloxone -It is a competitive pure antagonist. -It has high affinity to block μ-receptors, less affinity to block κ-receptors -It is very weak in blocking δ-receptors. -It is used only by I.V. injection due to extensive first pass metabolism, with duration of action l-4 h. Uses 1- Treatment of acute opioid poisoning in non-addicts (it is not used in addicts as can precipitate fatal withdrawal syndrome). 2- Treatment of neonatal asphyxia induced by morphine. 3- Diagnosis of the cases of opioid addiction. V- Pure opioid antagonists Naltrexone - It differs from naloxone in: 1-It is used only orally (more bioavailable). 2-It has longer duration of action (24 h). 3-It is more potent than naloxone. Uses: 1- as maintenance treatment for acute opioid poisoning. 2- in ex-abusers to opioids to prevent readdiction by blocking the effect of self-administered opioids. 3- given to physicians, nurses and pharmacists who contact with opioids to protect them from the risk of addiction. 4- Treatment of alcoholism. Nalmefene - It is a new agent, which is a derivative of naltrexone but used I.V. with duration 8-10 h.