Opioid Analgesics

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Chapter: Essential pharmacology : Opioid Analgesics And Antagonists

A dark brown, resinous material obtained from poppy (Papaver somniferum) capsule. It contains two types of alkaloids.


OPIOID ANALGESICS

 

Opium

 

A dark brown, resinous material obtained from poppy (Papaver somniferum) capsule. It contains two types of alkaloids.



 

Phenanthrene Derivatives

Morphine (10% in opium)

Codeine (0.5% in opium)

Thebaine (0.2% in opium), (Nonanalgesic)

 

Benzoisoquinoline Derivatives

Papaverine (1%) (Nonanalgesic)

Noscapine (6%) (Nonanalgesic)

 

Opium has been known from the earliest times. It is mentioned in the Eber’s papyrus (1500 BC), in the writings of Theophrastus (300 BC) and Galen (2nd century AD). Opium eating became a social custom in China in the 18th century. Serturner, a pharmacist, isolated the active principle of opium in 1806 and named it ‘morphine’ after the Greek god of dreams Morpheus. In the last century a large number of semisynthetic and synthetic compounds have been developed with morphinelike, antagonistic and mixed agonistic-antagonistic properties.

 

Morphine

 

Morphine is the principal alkaloid in opium and still widely used. Therefore, it is described as prototype.

 

Pharmacological Actions

 

1. CNS

 

Morphine has site specific depressant and stimulant actions in the CNS by interacting primarily with the μ opioid receptor as a full agonist. The depressant actions are:

 

Analgesia Morphine is a strong analgesic. Though dull, poorly localized visceral pain is relieved better than sharply defined somatic pain; higher doses can mitigate even severe pain—degree of analgesia increasing with dose. Nociceptive pain arising from stimulation of peripheral pain receptors is relieved better than neuretic pain (such as trigeminal neuralgia) due to inflammation of or damage to neural structures. The associated reactions to intense pain (apprehension, fear, autonomic effects) are also dampened. Suppression of pain perception is selective, without affecting other sensations or producing proportionate generalized CNS depression (contrast general anaesthetics).

 

Perception of pain and its emotional or suffering component are both altered so that pain is no longer as unpleasant or distressing, i.e. the patient tolerates pain better. The analgesic action of morphine has spinal and supraspinal components. Intrathecal injection has been shown to cause segmental analgesia without affecting other modalities. It acts in the substantia gelatinosa of dorsal horn to inhibit release of excitatory transmitters from primary afferents carrying pain impulses. The action appears to be exerted through interneurones which are involved in the ‘gating’ of pain impulses. Release of glutamate from primary pain afferents in the spinal cord and its postsynaptic action on dorsal horn neurones is inhibited by morphine. Action at supraspinal sites in medulla, midbrain, limbic and cortical areas may alter processing and interpretation of pain impulses as well as send inhibitory impulses through descending pathways to the spinal cord. Several aminergic and other neuronal systems appear to be involved in the action of morphine. Simultaneous action at spinal and supraspinal sites greatly amplifies the analgesia.

 

Sedation which is different from that produced by hypnotics is seen. Drowsiness and indifference to surroundings as well as to own body occurs without motor incoordination, ataxia or apparent excitement (contrast alcohol). Higher doses progressively induce sleep and coma. Morphine has no anticonvulsant action, rather, fits may be precipitated.

 

Mood and Subjective Effects These are prominent. Morphine has a calming effect; there is loss of apprehension, feeling of detachment, lack of initiative, limbs feel heavy and body warm, mental clouding and inability to concentrate occurs. In the absence of pain or apprehension, these are generally appreciated as unpleasant by normal people. However, patients in pain or anxiety, and especially addicts, perceive it as pleasurable floating sensation: refer it as ‘high’. Rapid i.v. injection by addicts gives them a ‘kick’ or ‘rush’ which is intensely pleasurable—akin to orgasm. Thus, one has to learn to perceive the euphoric effect of morphine.

 

The pleasurable and reinforcing effects of μ opioid agonists (morphinelike) appear to involve a separate set of neuronal mechanisms than those involved in analgesia and sedation. The euphoric effects are most likely mediated by DA release in nucleus accumbance, whereas agonists (nalorphine like) inhibit DA release and produce aversion. Inhibition of NA release in locus ceruleus by opioids is implicated in their action to allay apprehension and fear.

 

Respiratory Centre Morphine depresses respiratory centre in a dose dependent manner; rate and tidal volume are both decreased: death in poisoning is due to respiratory failure. Neurogenic, hypercapnoeic and later hypoxic drives to the respiratory centre are suppressed in succession. In addition, there is indifference to breathing: apnoeic patient may breath if commanded.

 

Cough centre It is depressed; more sensitive to morphine than respiratory centre.

 

Temperature regulating centre It is depressed; hypothermia occurs in cold surroundings.

 

Vasomotor centre It is depressed at higher doses and contributes to the fall in BP.

 

Morphine Stimulates:

 

a)   CTZ Nausea and vomiting occur as side effects, especially if stomach is full and the patient stands or moves about. Thus, morphine appears to sensitize the CTZ to vestibular and other impulses. Larger doses depress vomiting centre directly: emetics should not be tried in morphine poisoning.

 

b)      Edinger Westphal Nucleus of III nerve is stimulated producing miosis. This is a central action; no miosis occurs on topical application of morphine to the eye. Mydriasis occurs in some species like cats. Other ocular effect is a decrease in intraocular tension.

 

c)   Vagal centre It is stimulated bradycardia is the usual response.

 

d)  Certain Cortical Areas and Hippocampal cells are stimulated. Excitation is seen in an occasional individual. Muscular rigidity and immobility is consistently manifested at high doses (especially on i.v. injection): resembles catalepsy seen in rats and mice. Convulsions may occur in morphine poisoning. The proconvulsant action has been ascribed to inhibition of GABA release by hippocampal interneurones. Species like cat, lion, horse, sheep and cow are uniformly excited and show hyperthermia.

 

2. Neuroendocrine

 

Hypothalamic activation by afferent collaterals is dampened. Hypothalamic influence on pituitary is reduced. As a result FSH, LH, ACTH levels are lowered, while prolactin and GH levels are raised (these are under predominant inhibitory control). The sex hormone and corticosteroid levels are lowered in the short term, but tolerance develops in the long term. Only few chronic abusers suffer from infertility; hypocorticism is not a problem in them. Morphine can release ADH and reduce urine volume.

 

3. CVS 

 

Morphine causes vasodilatation due to:

 

(a) histamine release.

(b) depression of vasomotor centre.

(c) direct action decreasing tone of blood vessels. There is a shift of blood from pulmonary to systemic circuit due to greater vasodilatation in the latter. Therapeutic doses cause little change in the BP of recumbent normovolaemic patient. Postural hypotension and fainting do occur due to impairment of vascular reflexes. Morphine has little  direct  effect  on  heart;  rate  generally decreases due to stimulation of vagal centre, but may increase reflexly if the BP falls. Cardiac work is consistently reduced due to decrease in peripheral resistance. Intracranial tension tends to rise as a consequence of CO2 retention leading to cerebral vasodilatation.

 

4. GIT

 

Constipation is a prominent feature of morphine action. Several factors contribute:

 

(a) Action directly on intestines and in CNS increases tone and segmentation but decreases propulsive movements. Tone of duodenum and colon may be increased to the level of spasm.

(b) Spasm of pyloric, ileocaecal and anal sphincters.

(c) Decrease in all gastrointestinal secretions: reduction in transfer of water and electrolytes from mucosa to the lumen. Absorption of fluid is increased due to stasis.

(d) Central action causing inattention to defecation reflex.

No tolerance develops to this action: addicts remain chronically constipated.

 

5. Other Smooth Muscles

 

Biliary tract Morphine causes spasm of sphincter of Oddi intrabiliary pressure is increased may cause biliary colic. This action is only partly counteracted by atropine but more completely by opioid antagonist naloxone and direct smooth muscle relaxants like nitrates.

 

Urinary bladder Tone of both detrusor and sphincter is increased urinary urgency and difficulty in micturition. Contractions of ureter are also increased.

 

Uterus The action is clinically insignificant, may slightly prolong labour.

 

Bronchi Morphine releases histamine which can cause bronchoconstriction. This is of no consequence in normal individuals, but can be dangerous in asthmatics.

 

6. ANS

 

Morphine causes mild hyperglycaemia due to central sympathetic stimulation. It has weak anticholinesterase action.

 

Pharmacokinetics

 

The oral absorption of morphine is unreliable because of high and variable first pass metabolism; oral bioavailability is 1/6th to 1/4th of parenterally administered drug. About 30% is bound to plasma proteins. Distribution is wide; concentration in liver, spleen and kidney is higher than that in plasma. Only a small fraction enters brain rather slowly. Morphine freely crosses placenta and can affect the foetus more than the mother. It is primarily metabolized in liver by glucuronide conjugation. Morphine6glucuronide is an active metabolite (inherently more potent than morphine) which accumulates during chronic dosing and contributes to analgesia, despite its restricted passage across blood-brain barrier. Another metabolite morphine3glucuronide has neuroexcitatory property. Plasma t½ of morphine averages 2–3 hours. Effect of a parenteral dose lasts 4–6 hours. Elimination is almost complete in 24 hours and morphine is noncumulative. Small amounts may persist due to enterohepatic circulation.

 

Adverse Effects

 

1.   Side Effects Sedation, mental clouding, lethargy and other subjective effects which may even be dysphoric in some subjects; vomiting is occasional in recumbent patient; constipation is common. Respiratory depression, blurring of vision, urinary retention (especially in elderly male) are other side effects. BP may fall, especially in hypovolaemic patient and if he/she walks about.

 

2.    Idiosyncrasy and Allergy Allergy is uncommon and anaphylactoid reaction is rare. Urticaria, itch, swelling of lips are the manifestations. A local reaction at injection site may occur due to histamine release.

 

3.    Apnoea This may occur in the newborn when morphine is given to the mother during labour. The bloodbrain barrier of foetus is undeveloped, morphine attains higher concentration in foetal brain than in that of mother. Naloxone 10 μg/kg injected in the umbilical cord is the treatment of choice.

 

4.  Acute Morphine Poisoning It is accidental, suicidal or seen in drug abusers. In the nontolerant adult, 50 mg of morphine i.m. produces serious toxicity. The human lethal dose is estimated to be about 250 mg. Manifestations are extensions of the pharmacological action.

 

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 (positive pressure respiration also decreases pulmonary edema formation) and maintenance of BP (i.v. fluids, vasoconstrictors). Gastric lavage should be done with pot. permanganate to remove unabsorbed drug. Lavage is indicated even when morphine has been injected; being a basic drug it is partitioned to the acid gastric juice, ionizes there and does not diffuse back into blood.

 

Specific antidote: Naloxone 0.4–0.8 mg i.v. repeated every 2–3 min till respiration picks up, is the preferred specific antagonist because it does not have any agonistic action and does not per se depress respiration. It has a short duration of action. Injection should be repeated every 1–4 hours later on, according to the response. Nalorphine is no longer used.

 

5. Tolerance And Dependence High degree of tolerance can be developed to morphine and related opioids if the drug is used repeatedly. It is partly pharmacokinetic (enhanced rate of metabolism), but mainly pharmacodynamic (cellular tolerance). Tolerance is exhibited to most actions, but not to constipating and miotic actions. Addicts tolerate morphine in grams: lethal dose is markedly increased. Patients in intense pain are relatively tolerant to depressant effects. Cross tolerance among opioids is of high degree. Morphine tolerant subjects are partially cross tolerant to other CNS depressants as well.

 

Morphine produces pronounced psychological and physical dependence, its abuse liability is rated high. Recently the NMDA antagonists and nitric oxide synthase inhibitors have been found to block morphine tolerance and dependence in animals. Thus, analgesic action of morphine can be dissociated from tolerance and dependence which contribute to its abuse. 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 abuse is higher among medical and paramedical personnel. Earlier, morphine addicts tended to be from the middle age group, but now younger individuals are also opting for it. Opium eating has been prevalent among natives in the orient.

 

Withdrawal of morphine is associated with marked drug seeking behaviour. Physical manifestations 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 not a characteristic feature (contrast barbiturates) and are seen only occasionally. Cardiovascular collapse and fatality are rare if supportive measures are instituted.

 

Opioid antagonists (naloxone, nalorphine) precipitate acute withdrawal syndrome in the dependent subject. In the more severely dependent, even 0.2 mg of naloxone can precipitate marked withdrawal.

 

Treatment: consists of withdrawal of morphine and substitution with oral methadone (long-acting, orally effective) followed by gradual withdrawal of methadone. However, relapse rate among post-addicts is high. Long-term methadone maintenance and other techniques using agonist-antagonistic drugs are also employed.

 

Precautions And Contraindications

 

Morphine is a drug of emergency, but due care has to be taken in its use.

 

·   Infants and the elderly are more susceptible to the respiratory depressant action of morphine.

 

·  It is dangerous in patients with respiratory insufficiency (emphysema, pulmonary fibrosis, cor pulmonale), sudden deaths have occurred.

 

·      Bronchial asthma: Morphine can precipitate an attack by its histamine releasing action.

 

·      Head injury: morphine is contraindicated in patients with head injury. Reasons are—

 

(a) By retaining CO2, it increases intracranial tension which will add to that caused by head injury itself.

(b) Even therapeutic doses can cause marked respiratory depression in these patients.

(c) Vomiting, miosis and altered mentation produced by morphine interfere with assessment of progress in head injury cases.

 

·      Hypotensive states and hypovolaemia exaggerate fall in BP due to morphine.

 

·   Undiagnosed acute abdominal pain: morphine can aggravate certain conditions, e.g. diverticulitis, biliary colic, pancreatitis. Inflamed appendix may rupture. Morphine can be given after the diagnosis is established. Pentazocine, buprenorphine are less likely to aggravate biliary spasm.

 

·      Elderly male: chances of urinary retention are high.

 

·      Hypothyroidism, liver and kidney disease patients are more sensitive to morphine.

 

·      Unstable personalities: are liable to continue with its use and become addicted.

 

Interactions

 

Phenothiazines, tricyclic antidepressants, MAO inhibitors, amphetamine and neostigmine potentiate morphine and other opioids, either by retarding its metabolism or by a pharmacodynamic interaction at the level of central neurotransmitters.

 

Morphine retards absorption of many orally administered drugs by delaying gastric emptying.

 

Dose: 10–50 mg oral, 10–15 mg i.m. or s.c. or 2–6 mg i.v.; 2–3 mg epidural/intrathecal; children 0.1–0.2 mg/kg.

 

MORPHINE SULPHATE 10 mg/ml inj; MORCONTIN 10, 30, 60, 100 mg continuous release tabs; 30–100 mg BD; RILIMORF 10, 20 mg tabs, 60 mg SR tab.

 

CLASSIFICATION OF OPIOIDS

 

1. Natural opium alkaloids: Morphine, Codeine

2. Semisynthetic opiates: Diacetylmorphine (Heroin), Pholcodeine.

Many others like—Hydromorphone, Oxymorphone, Hydrocodone, Oxycodone, are not used in India.

3. Synthetic opioids: Pethidine (Meperidine), Fentanyl, Methadone, Dextropropoxyphene, Tramadol.

 

Many others like—Levorphanol, Dextromoramide, Dipipanone, Alfentanil, Sufentanil, Remifentanil are not available in India.

 

Codeine

 

It is methylmorphine, 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; is a partial agonist at μ opioid receptor with a low ceiling effect. The degree of analgesia is comparable to aspirin (60 mg codeine ~ 600 mg aspirin); can relieve mild to moderate pain only.

 

However, it is more selective cough suppressant (only 1/3rd as potent as morphine); subanalgesic doses (10–30 mg) suppress cough (see p. 214). Codeine has very low affinity for opioid receptors. The analgesic action has been ascribed to morphine generated by its demethylation by CYP2D6; codeine fails to produce analgesia in subjects with polymorphic CYP2D6. However, receptors involved in antitussive action appear to be distinct, because they bind codeine as well as morphine.

 

Codeine has good activity by the oral route (oral: parenteral ratio 1:2). A single oral dose acts for 4–6 hours. Constipation is a prominent side effect when it is used as analgesic. Codeine has been used to control diarrhoea (see Ch. No. 48). Other side effects are milder. The abuse liability is low. Though codeine phosphate is water soluble and can be injected, parenteral preparation is not available.

 

Pholcodeine

 

It has codeine like properties and has been used mainly as antitussive; claimed to be less constipating.

 

Heroin

(Diamorphine, Diacetylmorphine)

 

It is about 3 times more potent than morphine; more lipid soluble: enters brain more rapidly but duration of action is similar. It is considered to be more euphorient (especially on i.v. injection) and highly addicting. Because of its high potency, it has been favoured in illicit drug trafficking. The sedative, emetic and hypotensive actions are said to be less prominent. However, it has no outstanding therapeutic advantage over morphine and has been banned in most countries except U.K.

 

Pethidine (Meperidine)

 

Pethidine was synthesized as an atropine substitute in 1939, and has some actions like it. Though chemically unrelated to morphine, it interacts with opioid receptors and its actions are blocked by naloxone. Important differences in comparison to morphine are:

 

·      Dose to dose 1/10th in analgesic potency; however, analgesic efficacy approaches near to morphine and is greater than codeine.

 

·      After i.m. injection, the onset of action is more rapid but duration is shorter (2–3 hours).

 

·      It does not effectively suppress cough.

 

·      Spasmodic action on smooth muscles is less marked—miosis, constipation and urinary retention are less prominent.

 

Pethidine is believed to induce less biliary spasm than morphine; traditionally preferred in cholecystitis/biliary colic. However, there is no objective evidence to support this belief. One study* in patients undergoing cholecystectomy found pethidine to raise common bile duct pressure 14% more than equianalgesic dose of morphine.



 

·   It is equally sedative and euphoriant, has similar abuse potential. The degree of respiratory depression seen at equianalgesic doses is equivalent to morphine.

 

·      Tachycardia (due to antimuscarinic action) occurs instead of bradycardia.

 

·      It causes less histamine release and is safer in asthmatics.

 

·      It has local anaesthetic action: corneal anaesthesia is seen after systemic doses.

 

·      It is well absorbed, oral: parenteral activity ratio is high (1/3 to 1/2). Pethidine is nearly completely metabolized in liver. The plasma t½ of pethidine is 2–3 hours. Acidification of urine increases excretion of unchanged pethidine.

 

Side Effects

 

These are similar to morphine except those mentioned above. Some atropinic effects (dry mouth, blurred vision, tachycardia) may be noted in addition.

 

Overdose of pethidine produces many excitatory effects—tremors, mydriasis, hyperreflexia, delirium, myoclonus and convulsions. This is due to accumulation of norpethidine which has excitant effects. Renal failure patients given repeated doses of pethidine may also experience similar effects.

 

Nonselective MAO inhibitors interfere with hydrolysis but not with demethylation of pethidine—norpethidine is produced in excess and excitement occurs.

 

Tolerance and physical dependence develop slowly with pethidine. Probably due to its shorter duration of action, body functions get time to recover. For the same reason withdrawal syndrome develops more rapidly. Autonomic disturbances are less marked during pethidine withdrawal, than after morphine withdrawal.

 

Use

 

Pethidine is primarily used as an analgesic (substitute of morphine) and in preanaesthetic medication, but not for cough or diarrhoea. It has also been used to control shivering during recovery from anaesthesia or that attending i.v. infusions. Potential adverse effects due to accumulation of norpethidine limit its utility in patients who require repeated dosing. It is the preferred opioid analgesic during labour—at equianalgesic doses neonatal respiratory depression is less marked, but still significant.

 

Dose: 50–100 mg i.m., s.c. (may cause irritation, local fibrosis on repeated injection), occasionally given orally or i.v.

 

PETHIDINE HCL 100 mg/2 ml inj; 50, 100 mg tab.

 

Fentanyl

 

A pethidine congener, 80–100 times more potent than morphine, both in analgesia and respiratory depression. In analgesic doses it produces few cardiovascular effects; has little propensity to release histamine. Because of high lipid solubility, it enters brain rapidly and produces peak analgesia in 5 min after i.v. injection. The duration of action is short: starts wearing off after 30–40 min due to redistribution, while elimination t½ is ~4 hr. In the injectable form it is almost exclusively used in anaesthesia (see p. 376). Transdermal fentanyl has become available for use in cancer or other types of chronic pain for patients requiring opioid analgesia.

 

DUROGESIC transdermal patch delivering 25 μg/hr, 50 μg/hr or 75 μg per hour; the patch is changed every 2–3 days.

 

Methadone

 

A synthetic opioid, chemically dissimilar but pharmacologically very similar to morphine—has analgesic, respiratory depressant, emetic, antitussive, constipating and biliary actions similar to morphine.

 

The most important feature of methadone is high oral: parenteral activity ratio (1 : 2) and its firm binding to tissue proteins. In single doses it is only slightly more potent than morphine and has comparable duration of action (4–6 hours on i.m. injection), but it cumulates in tissues on repeated administration—duration of action is progressively lengthened due to gradual release from these sites; plasma t½ on chronic use is 24– 36 hours. Plasma protein binding is 90% and it is metabolized in liver, primarily by demethylation and cyclization—metabolites are excreted in urine. Rifampin and phenytoin can cause withdrawal symptoms to appear in methadone dependent subjects by inducing its metabolism.

 

Because of slow and persistent nature of action, sedative and subjective effects are less intense. It is probably incapable of giving a ‘kick’. The abuse potential is rated lower than morphine. Tolerance develops more slowly, probably due to progressive filling of tissue stores. Withdrawal syndrome is of gradual onset, taking 1–2 days after discontinuation, is prolonged and less severe.

 

Methadone has been used primarily as substitution therapy of opioid dependence: 1 mg of oral methadone can be substituted for 4 mg of morphine, 2 mg of heroin and 20 mg of pethidine. Another technique is methadone maintenance therapy in opioid addicts—sufficient dose of methadone is given orally to produce high degree of tolerance so that pleasurable effects of i.v. doses of morphine or heroin are not perceived and the subject gives up the habit.

 

It can also be used as an analgesic for the same conditions as morphine; dose 2.5–10 mg oral or i.m. but not s.c. It is occasionally employed as antitussive.

 

PHYSEPTONE 10 mg inj, 2 mg/5 ml linctus.

 

 

Dextropropoxyphene

 

It is chemically related to methadone but is quite similar in analgesic action and in side effects to codeine, except that it is a poor antitussive and probably less constipating. It is nearly ½ as potent as codeine and has a lower oral: parenteral activity ratio. It is metabolized in liver; t½ is variable (4–12 hours). Delirium and convulsions have occurred in overdose. The demethylated metabolite of propoxyphene is cardiotoxic. The abuse liability is similar to or lower than codeine.

 

Dextropropoxyphene (60–120 mg) is used as a mild oral analgesic. It is marketed only in combination with paracetamol ± other drugs; but the contribution of dextropropoxyphene to the analgesic effect of the combination is questionable. The cardiac toxicity of its demethylated metabolite and seizures are dangerous in overdose; only partly antagonized by naloxone. Because of reported fatalities and no clear advantage of the combinations over paracetamol alone, such preparations have been withdrawn in the UK, but are quite popular in India, USA, etc, probably due to the perceived addictive potential of codeine.

 

PARVODEX 60 mg cap: PARVON, PROXYVON, WALAGESIC: dextropropoxyphene 65 mg + paracetamol 400 mg cap; WYGESIC, SUDHINOL 65 mg + paracetamol  650  mg  cap.

 

Tramadol

 

This centrally acting analgesic relieves pain by opioid as well as additional mechanisms. Its affinity for μ opioid receptor is low, while that for κ and δ is very low. Unlike other opioids, it inhibits reuptake of NA and 5HT, and thus activates monoaminergic spinal inhibition of pain. Its analgesic action is only partially reversed by the opioid antagonist naloxone.

 

Injected i.v. 100 mg tramadol is equianalgesic to 10 mg i.m. morphine; oral bioavailability is good (oral: parenteral dose ratio is 1.4). The t½ is 5 hours and effects last for 4–6 hrs. Tramadol causes less respiratory depression, sedation, constipation, urinary retention and rise in intra-biliary pressure than morphine. It is well tolerated; side effects are dizziness, nausea, sleepiness, dry mouth, sweating and lowering of seizure threshold. Haemodynamic effects are minimal.

 

Tramadol is indicated for mild to moderate short-lasting pain due to diagnostic procedures, injury, surgery, etc, as well as for chronic pain including cancer pain, but is not effective in severe pain. Little tendency to dose escalation is seen and abuse potential is low.

 

Dose: 50–100 mg oral/i.m./slow i.v. infusion (children 1–2 mg/kg) 4–6 hourly.

 

CONTRAMAL, DOMADOL, TRAMAZAC 50 mg cap, 100 mg SR tab; 50 mg/ml inj in 1 and 2 ml amps.

 

Uses (Of Morphine and its congeners).

 

As analgesic

 

Opioid analgesics are indicated in severe pain of any type. However, they only provide symptomatic relief without affecting the cause. Pain may be valuable for diagnosis: should not be relieved by analgesic unless proper assessment of the patient has been done. Indiscriminate use of opioids can be hazardous. On the other hand, inadequate dose or reluctance to use these drugs in a patient in distress is equally deplorable.

 

Morphine or one of its parenteral congeners is indicated especially in traumatic, visceral, ischaemic (myocardial infarction), postoperative, burn, cancer pain and the like. It should be given promptly in myocardial infarction to allay apprehension and reflex sympathetic stimulation. Opioids, especially pethidine, have been extensively used for obstetric analgesia, but one must be prepared to deal with the foetal and maternal complications.

 

Adequate use of morphine (even i.v.) is indicated in an emergency. It may prevent neurogenic shock and other autonomic effects of excruciating pain. Opioids should not be restricted in case of pain of terminal illness (cancer pain), but for other chronic conditions, due consideration must be given to their addicting liabilities. Neuropathic pain responds less predictably to opioid analgesics.

 

Epidural (2–3 mg) or intrathecal (0.2 mg) injection of morphine produces segmental analgesia lasting ~12 hour without affecting other sensory, motor or autonomic modalities. It is being used for surgical analgesia in abdominal, lower limb and pelvic operations as well as for labour, postoperative, cancer and other intractable pain. Respiratory depression occurs after a delay due to ascent of the opioid through the subarachnoid space to the respiratory centre. Use of fentanyl in place of morphine produces faster analgesia and reduces the risk of respiratory depression because of greater uptake by nerves at the site of injection.

 

Patient controlled analgesia (PCA) is an attractive technique of postoperative pain control in which the patient himself regulates the rate of i.v. fentanyl infusion according to intensity of pain felt.

 

Transdermal fentanyl is a suitable option for chronic cancer and other terminal illness pain. The patch produces analgesia after ~12 hr, but then blood levels of fentanyl and intensity of analgesia remain fairly uniform if the patch is changed every 2–3 days.

 

For milder pain, e.g. toothache, headache, neuralgias, etc., aspirin-like analgesics are preferred. When they are not effective—codeine/ dextropropoxyphene may be used orally, either alone or in combination with aspirin-like drug. The combination enhances the ceiling analgesia. For majority of painful conditions, especially more severe and longer-lasting pain, a NSAID should be combined with the opioid; helps to enance analgesia while keeping the opioid dose low.

 

Preanaesthetic Medication

 

Morphine and pethidine are used in few selected patients.

 

Balanced Anaesthesia And Surgical Analgesia

 

Fentanyl, morphine, pethidine, alfentanil or sufentanil are an important component of anaesthetic techniques.

 

Relief Of Anxiety And Apprehension

 

Especially in myocardial infarction, internal bleeding (haematemesis, threatened abortion, etc.) morphine or pethidine have been employed. However, they should not be used as anxiolytics or to induce sleep.

 

Acute Left Ventricular Failure (Cardiac Asthma)

 

Morphine (i.v.) affords dramatic relief by—

 

Reducing preload on heart due to vasodilatation and peripheral pooling of blood.

Tending to shift blood from pulmonary to systemic circuit; relieves pulmonary congestion and edema.

Allays air hunger by depressing respiratory centre.

Cuts down sympathetic stimulation by calming the patient, reduces cardiac work.

 

It is also indicated to relieve pulmonary edema due to infarction of lung and other causes, but not due to irritant gases. It is contraindicated in bronchial asthma.

 

Cough

 

Codeine or its substitutes are widely used for suppressing dry, irritating cough (see Ch. No. 16).

 

Diarrhoea

 

The constipating action of codeine has been used to check diarrhoea and to increase the consistency of stools in colostomy. Synthetic opioids exclusively used as antidiarrhoeals are diphenoxylate and loperamide. The risk and benefits of their use are detailed in Ch. No. 48.

 

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