(Narcotic analgesics) Non-opioid
(Nonsteroidal antiinfl ammatory 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.
Classifi cation 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) Dysphoria
Psychotomimetic effect Dependence
Respiratory depression
Analgesia (spinal and supraspinal level) Respiratory depression Proconvulsant action
Analgesia (spinal and supraspinal level) Euphoria Miosis Sedation Dependence Respiratory depression Inhibition of GI motility
Opioid Agonists
Mechanism of actionMorphine 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.
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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 effi cacious 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.
Fear Anxiety Apprehension
(reaction to pain) Sick feeling associated
with illness (because of euphoriant effect)
Morphine
relieves 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 CO2. 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-HT3 antagonists are the drugs of choice to control opioid-induced nausea
and vomiting. H1-blockers, such as cyclizine or prochlorperazine may also be used. iii. Vagal centre: It stimulates vagal centre in the medulla and can cause bradycardia.
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 MARPHINE CVS*
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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.
Morphine causes Depression of VMC 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 fi rst- pass 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. Diffi culty 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,
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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 detoxifi cation 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. Specifi c antidote: Naloxone 0.4–0.8 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. 6.10 Competitive antagonism.
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 progress in head-injury patients.
(b) Morphine Respiratory depression CO2 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.
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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).