Opioid Analgesics and Antagonists PDF

Opioid Analgesics and Antagonists Dr. Anuroop Singhai Oral Surgery Division MORPHINE – Adverse effects Adverse effects 1. Sedation 2. Mental clouding 3. Lethargy 4. Dysphoria 5. Vomiting is occasional in recumbent patients 6. Constipation is common 7. Respiratory depression...

Opioid Analgesics and Antagonists Dr. Anuroop Singhai Oral Surgery Division MORPHINE – Adverse effects Adverse effects 1. Sedation 2. Mental clouding 3. Lethargy 4. Dysphoria 5. Vomiting is occasional in recumbent patients 6. Constipation is common 7. Respiratory depression 8. Blurring of vision 9. Urinary retention (especially in elderly males) 10. BP may fall, especially in hypovolaemic patient and if he/she walks about 11. Urticaria, itch, swelling of lips Acute morphine poisoning Acute morphine poisoning In the non-tolerant adult, 50 mg of morphine i.m. produces serious toxicity. Manifestations: These are extensions of pharmacological action, Viz., stupor or coma, flaccidity, shallow and occasional breathing, cyanosis, pinpoint pupil, fall in BP and shock, convulsions may be seen in few, pulmonary edema occurs at terminal stages, death is due to respiratory failure. Treatment: Consists of respiratory support and maintenance of BP by i.v. fluids, vasoconstrictors. Gastric lavage should be done with pot. permanganate to remove unabsorbed drug. Naloxone 0.4–0.8 mg i.v. repeated every 2–3 minutes till respiration picks up, is the specific antidote. It has a short duration of action. Injection should be repeated every 1–4 hours, according to response. Morphine – Tolerance and dependence High degree of tolerance can be developed to morphine and related opioids if the drug is used repeatedly. Cross tolerance among opioids is of high degree. Morphine produces pronounced psychological and physical dependence, its abuse liability is rated high. Concern about abuse has been a major limitation in the use of morphine, but appropriate medical use of morphine seldom progresses to dependence and abuse. Morphine – Tolerance and dependence Withdrawal of morphine: In dependent subjects is associated with marked drug seeking behaviour. Physical manifestations of abstinence are—lacrimation, sweating, yawning, anxiety, fear, restlessness, gooseflesh, mydriasis, tremor, insomnia, abdominal colic, diarrhoea, dehydration, rise in BP, palpitation and rapid weight loss. Delirium and convulsions are seen only occasionally. Treatment: Consists of withdrawal of morphine and substitution with oral methadone which is long acting and orally effective, followed by gradual withdrawal of methadone. However, relapse rate among post-addicts is high. Morphine – Precautions, Contraindications and Interactions Morphine is a drug of emergency, but due care has to be taken in its use. 1. Infants and the elderly are more susceptible to the respiratory depressant action of morphine. 2. Morphine is risky in patients with respiratory insufficiency (emphysema, pulmonary fibrosis, cor pulmonale), sudden deaths have occurred. 3. Bronchial asthma: Morphine can precipitate an attack by its histamine releasing action. 4. Head injury: morphine is contraindicated in patients with head injury. Reasons are— By retaining CO2, it increases intracranial tension which will add to that caused by head injury itself. Even therapeutic doses can cause marked respiratory depression in these patients. Vomiting, miosis and altered mentation produced by morphine interfere with assessment of progress in head injury cases. Morphine – Precautions, Contraindications and Interactions 5. Hypotensive states and hypovolaemia exaggerate fall in BP due to morphine. 6. Elderly male: chances of urinary retention are high. 7. Hypothyroidism, liver and kidney disease patients are more sensitive to morphine. 8. Unstable personalities: are liable to continue with its use and become addicted. Phenothiazines and tricyclic antidepressants potentiate morphine and other opioids, either by retarding its metabolism or by a pharmacodynamic interaction. Dose: Adult: 10 - 50 mg oral, 10 - 15 mg i.m. or s.c. or 2 - 6 mg i.v. Children: 0.1 - 0.2 mg/kg i.m. or s.c. Codeine It is methyl-morphine, occurs naturally in opium, and is partly converted in the body to morphine. It is less potent than morphine (1/10th as analgesic), also less efficacious, i.e. cannot relieve severe pain. The degree of analgesia is comparable to aspirin (60 mg codeine ~ 600 mg aspirin). However, codeine is a more selective cough suppressant (1/3rd as potent as morphine); subanalgesic doses (10–30 mg) suppress cough. Codeine has good activity by oral route. A single oral dose acts for 4–6 hours. Constipation is prominent, but other side effects are mild. It has been used to control diarrhoea. Tramadol This centrally acting analgesic is an atypical opioid which relieves pain by opioid as well as additional mechanisms. Pharmacokinetics: Oral bioavailability is good. The t1⁄2 is 3–5 hours and effects last for 4–6 hrs. Tramadol causes less respiratory depression, sedation, constipation, urinary retention and rise in intrabiliary pressure than morphine. Tramadol Adverse effects: It is well tolerated. Side effects are: 1. Dizziness 2. Nausea 3. Sleepiness 4. Dry mouth and sweating 5. Haemodynamic effects are minimal. Dose: 50–100 mg oral/i.m./slow i.v. infusion (children 1–2 mg/kg) 4–6 hourly. Opioids - Uses Uses: 1. As analgesic: Opioid analgesics are indicated in severe pain of any type. However, their use in dentistry is very limited. They only provide symptomatic relief without affecting the cause. Morphine and its parenteral congeners are indicated in traumatic, visceral, ischaemic (myocardial infarction), postoperative, burn, cancer pain. It should be given promptly in myocardial infarction to allay apprehension and reflex sympathetic stimulation. 2. Preanaesthetic medication: Morphine and pethidine are used in selected patients. 3. Balanced anaesthesia and surgical analgesia: Fentanyl, morphine or pethidine are an important component of anaesthetic techniques. Opioids - Uses 4. Relief of anxiety and apprehension: Specially in myocardial infarction, internal bleeding (haematemesis, threatened abortion, etc.) morphine or pethidine have been employed. 5. Acute left ventricular failure (cardiac asthma): Morphine (i.v.) affords dramatic relief. 6. Cough: Codeine or its substitutes are widely used for suppressing dry, irritating cough. 7. Diarrhoea: The constipating action of codeine, loperamide and diphenoxylate has been used to check diarrhoea. Opioids receptors Actions ascribed to different types of opioid receptors μ (mu) ! (kappa) " (delta) Analgesia Analgesia Sedation Respiratory depression Analgesia Euphoria Dysphoria Respiratory depression Miosis Hallucinations Affective behaviour Muscular rigidity Miosis Reinforcing actions Reduced g.i. motility Sedation Reduced g.i. motility Physical dependence Physical dependence Proconvulsant (morphine type) (nalorphine type) COMPLEX ACTION OPIOIDS AND OPIOID ANTAGONISTS 1. Agonist - antagonists (! analgesics) Nalorphine, Pentazocine, Butorphanol 2. Partial/weak μ agonist + ! antagonist Buprenorphine 3. Pure antagonists Naloxone, Naltrexone Buprenorphine It is a highly lipid-soluble μ analgesic that is 25 times more potent than morphine, but has lower ceiling effect. Onset of action is slower and duration longer. After a single dose, analgesia lasts for 6–8 hours; but with repeated intake, duration of action increases to ~24 hours due to accumulation of the drug in tissues. Sedation, vomiting, miosis, subjective and cardiovascular effects are similar to morphine, but constipation is less marked. Postural hypotension is prominent. Respiratory depression and analgesia exhibit ceiling effect. It substitutes for morphine at low levels of dependence but precipitates withdrawal in highly dependent subjects, reflecting its partial agonistic action at μ receptors. Buprenorphine Lower degree of tolerance and dependence (psychic as well as physical) develops with buprenorphine on chronic use. Its withdrawal syndrome resembles that of morphine but is delayed for several days, is milder and longer lasting. ‘Drug seeking’ is present. Abuse liability is rated lower than morphine. Naloxone (even high dose) only partially reverses buprenorphine effects and is unable to precipitate its withdrawal. Buprenorphine has good efficacy by sublingual route, is highly plasma protein bound and remains in tissues for several days; t1⁄2 is 40 hours. It is mostly excreted unchanged in bile. Dose: 0.3–0.6 mg i.m., s.c. or slow i.v., also sublingual 0.2–0.4 mg 6–8 hourly. Naloxone It is N-alylnor-oxymorphone and a competitive antagonist for all types of opioid receptors. Injected intravenously (0.4–0.8 mg) it promptly antagonizes all actions of morphine— analgesia is gone, respiration is not only normalized but even stimulated, and pupils dilate. At 4–10 mg dose, it also antagonizes the agonistic actions of ! analgesics (pentazocine). Actions of buprenorphine are prevented but not effectively reversed by naloxone, because it fails to displace buprenorphine that has already bound to the opioid receptors. Naloxone Naloxone 0.4 mg i.v. precipitates morphine withdrawal in dependent subjects: the syndrome lasts for 2–3 hours. Naloxone is inactive orally because of high first pass metabolism in liver. Injected i.v. it acts in 2–3 min. Plasma t1⁄2 is 1 hour in adults and 3 hours in newborns. NARCOTAN 0.4 mg in 1 ml (adult) and 0.04 mg in 2 ml (infant) amps; NALOX, NEX 0.4 mg inj. Use: Naloxone is the drug of choice for morphine poisoning (0.4–0.8 mg i.v. every 2–3 min: max 10 mg) and for reversing neonatal asphyxia due to opioid use during labour. Thank You