Analgesics OPIOID ANALGESICS

Transcription

1 Analgesics Opioid (Narcotic analgesics) Non-opioid (Nonsteroidal antiinflammatory drugs) OPIOID ANALGESICS Morphine is the most important alkaloid of opium the dried juice obtained from the capsules of Papaver somniferum. Opium contains many other alkaloids, e.g. codeine, thebaine, papaverine, etc. The term opiates refers to drugs derived from opium poppy, whereas opioid analgesic applies to any substance (endogenous peptides or drugs) that produces morphine-like analgesia. Classification of opioids 1. Opioid agonists a. Natural opium alkaloids: Morphine, codeine, thebaine*, papaverine*, nos capine*. b. Semisynthetic opiates: Heroin, pholcodine*, hydromorphone, oxymorphone. c. Synthetic opioids: Pethidine, tramadol, methadone, dextropropoxyphene, fentanyl, alfentanil, sufentanil, remifentanil. 2. Opioid agonist antagonists: Pentazocine, butorphanol. 3. Partial μ-receptor agonist: Buprenorphine. Opioid Receptor The three main types of opioid receptors are (mu), (kappa) and (delta). These receptor-mediated effects are given below. Opioid receptors Analgesia (spinal and supraspinal level) Euphoria Miosis Sedation Dependence Respiratory depression Inhibition of GI motility Analgesia (spinal and supraspinal level) Dysphoria Psychotomimetic effect Dependence Respiratory depression Analgesia (spinal and supraspinal level) Respiratory depression Proconvulsant action Opioid Agonists Mechanism of action Morphine and other opioids produce their actions by interacting with various opioid receptors mu (μ), delta () and kappa (). They are located at spinal and supraspinal levels (medulla, midbrain, limbic system and cortical areas) and peripheral nerves. Morphine is the prototype drug. * Have no analgesic activity. 1

2 Pharmacological actions of morphine Morphine has mainly CNS depressant effects; it also stimulates certain sites in the CNS. 1. CNS a. The depressant effects are: i. Analgesic effect: Mediated mainly through μ-receptors at spinal and supraspinal sites, it is the most important action of morphine. It is a very potent and efficacious analgesic. It causes sedation, drowsiness, euphoria, makes the person calm and raises the pain threshold. Perception of pain and reaction to it (fear, anxiety and apprehension) are altered by these drugs. Moderate doses of morphine relieve dull and continuous pain, whereas sharp, severe intermittent pain such as traumatic or visceral pain requires larger doses of morphine. MARPHINE CVS* Miosis Analgesia Respiratory depression Physical and psychological dependence Histamine release, hypotension, hypothermia Itching Nausea and vomiting Euphoria Cough suppression, constipation Vagal stimulation (bradycardia) Sedation and hypnosis Sick feeling associated with illness (because of euphoriant effect) Pain Morphine relieves Fear Anxiety Apprehension (reaction to pain) Therefore, morphine relieves total pain. ii. Euphoria (feeling of well-being): It is an important component of analgesic effect. Anxiety, fear, apprehension associated with painful illness or injury are reduced by opioids. iii. Sedation: Morphine, in therapeutic doses, causes drowsiness and decreases the physical activity. iv. Respiratory depression: It depresses respiration by a direct effect on the respiratory centre in the medulla; both rate and depth are reduced because it reduces sensitivity of the respiratory centre to CO 2. Respiratory depression is the commonest cause of death in acute opioid poisoning. v. Cough suppression: It has a direct action on cough centre in the medulla. vi. Hypothermia: In high doses, morphine depresses temperature-regulating centre and produces hypothermia. b. The stimulant effects are: i. Miosis: Morphine produces constriction of the pupils due to stimulation of III cranial nerve nucleus. Some tolerance develops to this action. Pinpoint pupils are an important feature in acute morphine poisoning. Miosis is not seen on topical application of morphine to the eye. ii. Nausea and vomiting: It is due to direct stimulation of the chemoreceptor trigger zone (CTZ) in the medulla. 5-HT 3 antagonists are the drugs of choice to control opioid-induced nausea and vomiting. H 1 -blockers, such as cyclizine or prochlorperazine may also be used. iii. Vagal centre: It stimulates vagal centre in the medulla and can cause bradycardia. *Mnemonic for actions of morphine: MARPHINE CVS. 2

3 c. Other effects i. Physical and psychological dependence: Repeated use of opioids causes physical and psychological dependence. ii. Histamine release: Morphine is a histamine liberator and causes skin rashes, urticaria, vasodilatation, bronchoconstriction, etc. iii. Itching can occur due to histamine release. 2. CVS: Morphine produces vasodilatation and fall of BP. Depression of VMC Morphine causes Histamine release Direct action on blood vessel Vasodilatation Hypotension It mainly causes vasodilatation of peripheral vessels, which results in shift of blood from pulmonary to systemic vessels leading to relief of pulmonary oedema associated with acute left ventricular failure. 3. GIT: It causes constipation by direct action on the GIT; the CNS action decreases GI motility and increases the tone of the sphincters. 4. Urinary bladder: It may cause urinary retention by increasing the tone of urethral sphincter. 5. Biliary tract: It increases intrabiliary pressure by increasing the tone of sphincter of Oddi. 6. Bronchi: It can cause bronchospasm by releasing histamine from the mast cells. Pharmacokinetics On oral administration, morphine is absorbed slowly and erratically. It also undergoes extensive firstpass metabolism; hence oral bioavailability of morphine is poor. Morphine is commonly administered by i.v., i.m. or s.c. routes. It can also be administered by oral, epidural or intrathecal routes. It is widely distributed in the body, crosses placental barrier and is metabolized in liver by glucuronide conjugation. Morphine-6-glucuronide has more potent analgesic action than morphine and is excreted in urine. Adverse effects 1. Nausea, vomiting and constipation. 2. Respiratory depression. 3. Hypotension due to vasodilatation. 4. Drowsiness, confusion and mental clouding. 5. Itching (due to histamine release) and skin rashes. 6. Difficulty in micturition. 7. Respiratory depression in newborn due to administration of morphine to the mother during labour. 8. Drug tolerance develops to most of the effects of morphine (some tolerance develops to miotic and constipating effects). There is cross-tolerance among the opioids. 9. Drug dependence (physical and psychological dependence) is the main drawback of opioid therapy. Psychological dependence is associated with intense craving for the drug. Physical dependence is associated with the development of withdrawal symptoms (abstinence syndrome) when administration of an opioid is stopped abruptly. The symptoms and signs are irritability, body shakes, jumping and other symptoms like yawning, lacrimation, sweating, fever, diarrhoea, 3

4 palpitation, insomnia, rise in BP, loss of weight, etc. (the symptoms are just opposite to morphine actions). Dependence is mediated through μ-receptors. Treatment of morphine dependence a. Hospitalization of the patient. b. Gradual withdrawal of morphine. c. Substitution therapy with methadone. Opioid agonist like methadone is preferred because: i. It is orally effective. ii. It has longer duration of action. iii. Withdrawal symptoms are mild. One milligram of methadone will substitute 4 mg of morphine. Later, methadone is gradually reduced and completely stopped within 10 days. Buprenorphine can also be used for treatment of opioid dependence. d. Pure opioid antagonist like naltrexone is used after detoxification to produce opioid blockade to prevent relapse in patients who have a sincere desire to leave the habit. It is the preferred antagonist because it is orally effective and has a long duration of action. e. Psychotherapy, occupational therapy, community treatment and rehabilitation. 10. Acute morphine poisoning: The characteristic triad of symptoms are respiratory depression, pinpoint pupils and coma. The other signs and symptoms are cyanosis, hypotension, shock and convulsions. Death is usually due to respiratory depression. Treatment of acute morphine poisoning a. Hospitalization. b. Maintain airway, breathing and circulation. c. Ventilatory support (positive pressure respiration). d. Gastric lavage with potassium permanganate. e. Specific antidote: Naloxone mg intravenously, dose is repeated till respiration becomes normal. Naloxone is a pure antagonist, competitively blocks opioid receptors and rapidly reverses respiratory depression (Fig. 6.10). The duration of action of naloxone is shorter; hence repeated administration is needed. Morphine (Agonist) Opioid receptors Naloxone (Antagonist) Fig Competitive antagonism. 4 Note: Administration of naloxone to morphine addicts should be done with caution because it may precipitate severe withdrawal symptoms. Contraindications 1. Head injury: Morphine is contraindicated in cases with head injury because: a. Vomiting, miosis and mental clouding produced by morphine interferes with assessment of (b) progress in head-injury patients. Morphine Respiratory depression CO 2 retention Cerebral vasodilation Intracranial tension. 2. Bronchial asthma: Morphine may precipitate an attack by histamine release. 3. Chronic obstructive pulmonary disease (COPD): It should be avoided in patients with low respiratory reserve emphysema, chronic bronchitis, cor pulmonale, etc. 4. Hypotensive states: It should be used cautiously in shock or when there is reduced blood volume.

5 5. Hypothyroidism and hypopituitarism: There is a prolonged and exaggerated response to morphine. 6. Infants and elderly: They are more prone to respiratory depressant effect of morphine. In elderly male, there are increased chances of urinary retention. 7. Undiagnosed acute abdominal pain: Morphine, if given before diagnosis, interferes with diagnosis by masking the pain. Its spasmogenic effect may aggravate the pain (biliary colic). Codeine: Natural Opium Alkaloid 1. Codeine has analgesic and cough-suppressant effects; is administered orally. 2. Compared to morphine: a. It is less potent as an analgesic. b. It has less respiratory depressant effect. c. It is less constipating. d. It has low addiction liability. 3. It has selective cough suppressant effect (antitussive); hence it is used to suppress dry cough. 4. It potentiates analgesic effect of aspirin and paracetamol. Codeine is used for relief of moderate pain. The main side effects are constipation and sedation. Pethidine (Meperidine) (Table 6.11) Pethidine can be administered by oral, i.v., s.c. and i.m. routes. It is well absorbed from the GI tract, but bioavailability is about 50% because of first-pass metabolism; widely distributed in the body, crosses placental barrier and metabolized in liver. The metabolites are excreted in urine. Table 6.11 Comparative Features of Morphine and Pethidine Morphine Natural opium alkaloid Analgesic dose: 10 mg i.m., i.v. (morphine is 10 times more potent) It produces sedation, euphoria, respiratory depression and drug addiction Effects on smooth muscles: 1. Constipation + 2. Biliary spasm + 3. Urinary retention + 4. Miosis + Has antitussive effect Releases histamine Pethidine (Meperidine) Synthetic opioid Analgesic dose: 100 mg i.m., i.v. (1/10 as potent as morphine) In equianalgesic doses, pethidine also produces same amount of sedation, euphoria, respiratory depression and drug addiction as morphine At times, pethidine can cause CNS stimulation with tremor, twitches and convulsions due to its metabolite, norpethidine Effect on smooth muscles: 1. Spasmodic effects constipation, biliary spasm, urinary retention, etc. are less prominent 2. Miosis is less prominent Has no signicant antitussive effect It causes less histamine release It has a rapid onset and longer duration of action (6 8 h) It has a rapid onset but shorter duration of action (3 4 h) Morphine causes severe respiratory depression in the newborn, when it is given to mother during labour Pethidine causes less respiratory depression in newborn 5

6 Adverse effects The adverse effects are similar to those of morphine. It can cause tremors, hallucinations, muscle twitches and rarely convulsions due to its metabolite, norpethidine. Tolerance, physical and psychological dependence can also develop with pethidine. Diphenoxylate: It is a pethidine congener and is used in the treatment of diarrhoea. It is available in combination with atropine. It is rarely used at present because of its dangerous side effect paralytic ileus. Loperamide: Loperamide is a pethidine congener. It reduces GI motility and secretions but increases the tone of the anal sphincter. It is used in the symptomatic treatment of diarrhoea. Common side effects are constipation and abdominal cramps. Therapeutic Uses of Morphine and its Congeners 1. As analgesic (Table 6.12 and Figure 6.11): Morphine and other opioids are very potent and efficacious analgesics; hence they are used for moderate-to-severe painful conditions, such as acute myocardial infarction (MI), burns, pulmonary embolism, fracture of mandible and long bones, bullet wound, etc. Opioids are also used to control severe pain in terminal stages of cancer. In renal and biliary colic, atropine is used with morphine to counteract the spasmogenic effect of morphine. Opioids are the preferred analgesics in severe painful conditions. Sustained release/long-acting opioid (SR oxycodone/sr morphine/transdermal fentanyl) + short-acting opioid ± non-opioid ± adjuvant* Short-acting opioid as required (morphine/oxycodone) ± non-opioid (paracetamol/nsaid) ± adjuvant* Non-opioid (paracetamol/nsaid) ± adjuvant* Step 3: Moderate to severe pain or pain uncontrolled after step 2 Step 2: Mild to moderate pain or pain uncontrolled after step 1 Step 1: Mild to moderate pain Fig World Health Organization analgesic ladder: *Adjuvants, e.g. carbamazepine, amitriptyline, diazepam, prednisolone, etc. Patient-controlled analgesia: This allows the patient to control the delivery of s.c., epidural or i.v. analgesic in a safe and effective way through a pump. The patient should inform the nurse when he takes a dose so that it can be replaced. 2. Preanaesthetic medication: Opioids like morphine and pethidine are used about half-an-hour before anaesthesia because of their sedative, analgesic and euphoric effects; the dose of anaesthetic required is reduced. 3. Acute pulmonary oedema (cardiac asthma): Intravenous morphine relieves breathlessness associated with acute left ventricular failure due to pulmonary oedema by: a. Reducing preload on heart by peripheral vasodilatation. b. Shifting the blood from pulmonary to systemic circulation. c. Reducing anxiety, fear and apprehension associated with the illness. 4. Postanaesthetic shivering: Pethidine is effective. 5. Cough: Codeine, pholcodine, dextromethorphan, etc. are commonly used for suppression of dry cough. 6. Diarrhoea: Synthetic opioids such as diphenoxylate and loperamide are used for symptomatic treatment of diarrhoea. 6

7 Other Opioids The route of administration, uses and some important features are represented in Table Table 6.12 Route of Administration, Uses and Some Important Points of Opioids Opioid Route of Administration Uses Tramadol Oral, i.v. In mild-moderate pain due to trauma and surgery In labour pain and cancer pain Fentanyl Fentanyl analogues Alfentanil Sufentanil Remifentanil Intravenous, epidural, intrathecal, transdermal patch Intravenously Used as analgesic to supplement anaesthetics (i.v.) In chronic pain and cancer pain (transdermal patch) Postoperative pain As analgesics perioperatively Methadone Oral, i.m. As substitution therapy in opioid-dependent subjects (see p. 180) For chronic pain Dextropropoxyphene Oral Used with paracetamol in moderate pain Pentazocine Oral, i.m., s.c. Traumatic and postoperative pain Butorphanol i.v., i.m. As an analgesic in postoperative pain Buprenorphine i.m., i.v., sublingual As an analgesic in postoperative pain, MI, cancer pain and preanaesthetic medication As substitution therapy in opioid dependent subjects Other Points Should be avoided in epileptics (it decreases seizure threshold) In patients on MAO inhibitors (may precipitate hypertensive crisis) Rapid acting and potent analgesic Minimal histamine release; Slight decrease in HR and BP Shorter acting than fentanyl More potent as analgesics than morphine Poor antitussive effect Analgesic effect is similar to codeine Acts on receptors Dysphoria, hallucinations, nightmares (psychotomimetic effect) can be reversed by naloxone Causes sympathetic stimulation tachycardia, palpitation, BP (contraindicated in patients with hypertension and ischaemic heart disease) Pharmacological actions and adverse effects are similar to pentazocine Causes cardiac stimulation and psychotomimetic effects Respiratory depression induced by buprenorphine cannot be reversed completely with naloxone; hence not used in labour pain Has long half-life 7

8 Tramadol It is a synthetic codeine derivative with weak agonistic activity at μ-receptors. It also inhibits the reuptake of noradrenaline and 5-HT. M A R P H I N E C V S * Pharmacological actions Tramadol causes: 1. Analgesia. 2. Respiratory depression. 3. Physical and psychological dependence. 4. Nausea and vomiting. Less than with equianalgesic doses of morphine 5. Euphoria. 6. Constipation. 7. Sedation. Fentanyl It is a synthetic opioid with a potent μ-agonistic effect (100 times more potent than morphine as an analgesic). Pharmacological actions are similar to morphine. Alfentanil, sufentanil and remifentanil are shortacting fentanyl analogues. They are useful for short procedures where intense analgesia is required. Methadone It is a synthetic opioid with agonistic effect at μ-receptors; has a long duration of action. Pharmacological actions are similar to morphine. M A R P H I N E C V S * 1. Miosis 2. Analgesia 3. Respiratory depression 4. Physical and psychological dependence 5. Nausea and vomiting 6. Euphoria 7. Cough suppression, constipation 8. Sedation Similar to morphine, but has less addiction liability Dextropropoxyphene It is structurally similar to methadone. The side effects are nausea, constipation, sedation, abdominal pain, etc. 8 *Line with downward arrow indicates that effect is less than morphine. The size of the arrows indicates degree of effect (smaller the size, lesser the effect).

9 .1 Opioid Antagonists: Naloxone, Naltrexone They are pure opioid antagonists. These drugs have no agonistic activity. Naloxone, naltrexone and nalmefene competitively reverse the effects of both natural and synthetic opioids, but they do not completely reverse buprenorphine induced respiratory depression. Naloxone also blocks analgesic effect of placebo and acupuncture, and effects of endogenous opioid peptides. Naloxone is orally not effective because of high first-pass metabolism. It is short acting. On i.v. administration, it immediately antagonizes all actions, especially respiratory depression of morphine and other opioids. Intravenous naloxone precipitates withdrawal symptoms in morphine and heroin addicts. Uses of naloxone 1. Main therapeutic use of naloxone is for the treatment of morphine and other opioid poisoning (see p. 180). 2. In the treatment of opioid overdosage, intravenous naloxone rapidly reverses the respiratory depression induced by opioids (except buprenorphine where it causes partial reversal of respiratory depression). 3. To treat neonatal asphyxia due to use of opioids in the mother during labour. Uses of naltrexone Naltrexone is orally effective and has longer duration of action. 1. Naltrexone is used for opioid-blockade therapy to prevent relapse in opioid-dependent individuals. 2. It is also used for the treatment of alcoholism, as it reduces the urge to drink. Nalmefene It is administered intravenously. It is long acting. Useful in the treatment of opioid overdosage. Endogenous Opioid Peptides Endorphins, enkephalins and dynorphins are naturally occurring substances present in the brain and other body tissues. They are called endogenous opiates because they resemble opium alkaloids (e.g. morphine) in their actions. These peptides appear to be involved in placebo and acupuncture-induced analgesia. Key Points for Dentists Morphine can cause vomiting. Chronic use of opioids causes dependence. Morphine is contraindicated in elderly and patients with head injury. Pentazocine is contraindicated in patients with ischaemic heart disease and hypertension. Patients receiving opioid analgesics for more than 1 or 2 days should be given a laxative. Oral or rectal route is preferred in children if they have to receive opioid analgesics for many days to avoid pain of injection. 9