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Opioid Analgesics

Opioid Analgesics: Pain (algesia) is an unpleasant, ill-defined subjective symptom. It is usually evoked by an external or internal noxious stimulus. The pain inducing endogenous substances are called algogenic agents. They are released during ischaemia, inflammation, tissue injury, and by thermal or mechanical stimuli. These algogenic agents are acetyicholine, histamine, kallidin, bradykinin and leukotrienes.

Bradykinin acts partly by releasing prostaglandins (PGs) which do not produce pain themselves but sensitize pain terminals to the action of other algogenic chemicals. Although pain causes discomfort, it is a warning signal and mainly protective in nature. Unbearable excessive pain may be associated with apprehension, nausea, palpitation, sweating, sinking sensation, techypnoea, and rise or fall in blood pressure. As a symptom, pain demands instant relief by drugs.

A drug that selectively relieves pain without significantly altering consciousness is called analgesic. An analgesic may achieve this goal by acting in the central nervous system or on peripheral pain mechanisms. Analgesics are classified into opioid(narcotic) and non-opioid (non-narcotic) groups.

OPIOID ANALGESICS

These are potent analgesics. Since they cause variable degree of sedation, they are also called narcotic analgesics. All of them act by stimulation of central opiate receptors {mu(j.t); kappa (K) and delta (ö)} which are widely distributed in central nervous system and other tissues. Subtypes of mu (i’ and J’2) and kappa (tc1 and 1(3) receptors have been identified. Morphine and its congeners have high affinity for mu receptors. The t1 has higher affinity for morphine. It mediates supraspinal analgesia and is selectively blocked by naloxone.

The has lower affinity for morphine. It mediates spinal analgesia, respiratory depression and constipation actions. The kappa agonists primarily cause spinal analgesia through its receptors while 1(3 receptors mediate lower ceiling supraspinal analgesia. The delta receptors are responsible to mediate spinal analgesia mainly. These receptors are also responsible for dependence reinforcing actions, proconvulsant action and gastrointestinal motility.

Endogenous opioid peptides (betaendorphin, enkephalins, and beta-dynorphin) have been identified. They are derived from distinct precursor polypeptides (proopiomelanocortin, proenkephalin, and prodynorphin respectively). In the central nervous system, they are believed to act as endogenous analgesics, as neurotransmitters and as behaviour modulators. In fact they form part of the complex-pain inhibiting mechanisms in the brain and spinal cord.

All opioid receptors are C-protein coupled receptors. These are situated mostly on prejunctional neurons. They generally cause inhibitory modulation. So they decrease release of the junctional transmitter such as noradrenaline, dopamine, 5-hydroxy- tryptamine, GABA, glutamate, etc.

Activation of opioid receptor decreases intracellular cAMP. This in turn opens up channels (mainly through aand 8 receptors) or suppresses voltage gated N type Ca channels (mainly K receptors). So there occurs neuronal hyperpolarization and reduction in intracellular Ca followed by decrease neurotransmitter release by central nervous system and myenteric neurons.

The sigma (a) receptor is no longer considered as opioid receptor. However, certain opioids (pentazocine, butorphanol, etc.) bind to this receptor and produce dysphoria, psychotomimetic action, tachycardia and mydriasis.

DRUGS ACTING ON OPIOID RECEPTORS

These drugs are classified as under on the basis of their receptor activity.

I. Agonists: They have main affinity for mu- receptors and some affinity for kappa and delta receptors.

1. Natural opium alkaloids: Morphine and codeine.

2. Semis ynthetic opiates: Heroin (diacetyl morphine), ethylmorphin, phlocodeine. (Not used in India: Hydromorphone, oxmorphone, hydrocodone, oxycodone).

3. Synthetic opioid: Pethidine (meperidine), fentanyl, methadone, dextropropoxyphene and ethoheptazine. (Not used in India: Alphaprodine, anileridine, dextromoramide, dipipanone, alfentanil, sulfentanil).

II. Mixed agonist antagonists: These have agonistic activity at kappa receptors and antagonistic effect on mu-receptors. They also have affinity for sigma-receptors.

1. Not used as analgesics: Nalorphine, levallorphan

2. Used as analgesics: Pentazocine, nalbuphine

3. Partial/weak agonists: Buprenorphine, butorphanol

Ill. Antagonists: These drugs mainly block mu-receptors. In higher doses, they also block kappa and delta receptors. They are naloxone and naltrexone.

Agonists

Opium alkaloids: Opium is obtained by incising the unripe seed capsule of the poppy plant, Papaver somniferum. On the basis of chemical structure, the pharmacologically active alkaloids can be divided into two groups:

1. Phenantherine alkaloids:

a. Morphine

b. Codeine

c. Thebaine.

2. Benzyl isoquinoline alkaloids (devoid of analgesic activity; act as smooth muscle relaxants):

a. Papaverine

b. Noscapine

c. Narcine

1. Morphine

It is the most important alkaloid of opium and will be discussed as prototype of this group.

Pharmacokinetics: On oral administration, the absorption of morphine from gut is slow and incomplete. Further, it is extensively metabolized during first pass through liver. Hence systemic availability is poor. It is, therefore, administered parenterally (i.m. or s.c.). On intramuscular administration, half-life is 2.5 hours. About 30% is bound to plasma proteins. Only a small fraction enters brain rather slowly. It freely crosses placenta. It is metabolized by N-dealkylation and oxidation, followed by glucuronide or sulfate conjugation. Approximately 90% (small amounts of free morphine and large amounts of conjugated morphine) is excreted in urine within 24 hours. A small amount of the drug is excreted in sweat. Seven to 10% of conjugated morphine appears in bile and is excreted in faeces.

Mechanism of action: Major pharmacological actions of morphine are due to its agonistic action on opioid receptors. Other pharmacological actions may be due to its influence on major neurotransmitter systems such as:

a. It releases histamine but inhibits the release of substance P.

b. It increases cholinergic and 5-I-IT activity.

c. It inhibits dopaminergic, noradrenergic and GABAergic activity.

Pharmacological Actions

Central nervous system: Morphine has site specific depressant and stimulant actions in the central nervous system.

Depressant effects:

i. Analgesia: Morphine relieves acute and chronic pain due to its effect on endogenous opioid receptors in supraspinal pain processing sites and on midbrain (periaqueductal grey) and brainstem (nucleus raphe megnus) areas. Due to its action at these sites, there occurs alteration in processing and interpretation of pain impulses. Further they send inhibitory impulses through descending pathways to the spinal cord. In addition morphine also acts directly on the dorsal horn, where it inhibits the release of substance P.

Morphine raises pain threshold and so it reduces the perception of pain. The patient frequently regards pain with detachment because it modifies the emotional reaction to pain. Euphoria and hypnosis produced by morphine may also help in raising the pain threshold.

ii. Euphoria: Morphine produces a marked sense of well-being, which is termed euphoria. It relieves anxiety and apprehension. Rarely morphine may produce restlessness, fear or anxiety which is termed as dysphoria. It is particularly seen in pain free individuals.

iii. Sedation is produced by morphine in analgesic doses and is useful when pain is accompanied by insomnia.

iv. Respiration: Morphine depresses respiratory center in a dose dependent manner

through its effect on mu-receptors. It decreases both rate and tidal volume. The cause of death in morphine poisoning is respiratory failure. Neurogenic, hypercapneic and later hypoxic drives to respiratory centers are suppressed in succession.

v. It depresses cough center, temperature regulating center (hypothermia occurs in cold surroundings) and vasomotor center (at higher doses).

Stimulant effects: Morphine stimulates the following centers/sites and leads to:

1. Vagal centre —+ bradycardia.

ii. Chemoreceptor trigger zone (CTZ) —* nausea and vomiting. However, larger doses of morphine depress the vomiting center directly; so emetics should not be used in acute morphine poisoning.

iii. Edinger-Westphal nucleus of III cranial nerve —> miosis; however, no miosis occurs on topical application.

iv. Certain cortical areas and hippocampus cells —> muscular rigidity and convulsions may occur in morphine poisoning.

Gastrointestinal tract: Morphine causes constipation which is due to:

• Spasm of duodenum and colon

• Decreased propulsive movements

• Spasm of pyloric, ileocaecal and anal sphincters.

• Inattention to defaecation reflex by its central action

• Decrease in all gastrointestinal secretions.

Since tolerance does not develop to this action, an addict remains chronically constipated.

OTher SmooTh Muscles

i. Bronchi: Morphine causes bronchoconstriction by releasing histamine.

ii. Biliary tract: Morphine produces:

• Spasm of sphincter of Oddi

• Increase in intrabiliary pressure

• Biliary colic

Atropine counteracts this action of morphine partially, while naloxone (opioid antagonist), nitrates and theophylline counteract it more completely.

iii. Uterus: It may slightly prolong labour.

iv. Urinary bladder: Morphine causes urinary urgency and difficulty in micturition by increasing the tone of both detrusor muscle and sphincter. It also increases the contractions of ureters.

Cardiovascular system: Morphine causes:

i. Vasodilatation due to:

• Depression of vasomotor centre

• Decreased tone of blood vessels by direct effect

• Histamine release

ii. Reduction in cardiac work due to decrease in peripheral resistance.

iii. Postural hypotension and fainting due to impairment of vascular reflexes. However, therapeutic doses cause little change in blood pressure of recumbent normovolemic patient.

iv. Shift of blood from pulmonary to systemic circuit due to greater vasodilatation in the latter.

v. Increase in intracranial tension due to CO2 retention. This then leads to cerebral vasodilatation.

vi. Heart rate may increase reflexly due to fall in UP or decrease due to stimulation of vagal centre.

Morphine produces slight fall in body temperature due to:

  • Decreased metabolic rate
  • Reduced respiratory rate
  • Decreased muscular activity
  • Peripheral vasodilatation

Miscellaneous

i. Morphine causes increased release of ADH and increased plasma prolactin levels.

ii. Morphine decreases release of ACTH, growth hormone and gonadotrophins.

iii. Morphine has immunosuppressant effect probably due to central action.

Therapeutic Uses

i. As analgesic: Morphine is indicated in severe pain of any type (burn, trauma, postoperative pain, and myocardial infarction). It is also used to relieve renal and intestinal colic with atropine). In routine, morphine is not used in chronic pain because it causes tolerance and physical dependence. However, it is employed to relieve pain associated with terminal cancer patients.

ii. Morphine may be used for preanaesthetic medication:

  • To allay anxiety and apprehension of the operation
  • To produce pre- and postoperative analgesia
  • To smoothen the induction
  • To reduce the dose of anesthetic required
  • To supplement poor analgesic (thiopentone, halothane) or weak (NO2) anesthetics
  • To reduce postoperative restlessness

iii. Acute left ventricular failure (cardiac asthma): Morphine (i.v.) affords dramatic relief by:

  • Inducing marked venodilatation and fall in preload
  • Arteriolar dilatation and fall in afterload
  • Relieving pulmonary congestion and oedema by shifting blood from pulmonary to systemic circuits
  • Allaying air hunger by causing depression of respiratory centre
  • Calming the patient, it cuts down sympathetic stimulation and reduces cardiac work

iv. Obsolete uses: It maybe used as anxiolytic, antidiarrhoeal and antitussive agent.

Dose: 10—15 mg i.m. or s.c. (rarely orally); or 2—10 mg i.v.; 2—3 mg epidural/ intrathecal; children 0.1—0.2 mg/kg.

Adverse effects: They may occur due to pharmacological actions of morphine. Important side effects are sedation, nausea, vomiting, mental clouding, lethargy, sweating, constipation, dysphoria, respiratory depression, blurring of vision, urinary retention, pruritus, piloerection, bradycardia, hypotension, bronchospasm.

Apnoea may occur in newborn when morphine is given to mother during labor because morphine attains higher concentration in fetal brain than in that of mother due to undeveloped blood—brain barrier.

Acute morphine poisoning may be accidental, suicidal or seen in drug addicts. Lethal dose is about 250 mg. Signs and symptoms are stupor or coma, cyanosis, pinpoint pupil, flaccidity, shallow and occasional breathing, convulsions, hypotension and shock. Pulmonary oedema occurs at terminal stages. Death is due to respiratory and circulatory failure. Treatment is given in the box.

Tolerance and Dependence

On repeated use, high degree of tolerance can be developed to morphine and related opioid. It is partly pharmacokinetic (enhanced rate of metabolism) but mainly pharmacodynamic (cellular tolerance). An addict can tolerate very high dose of morphine (500—600 mg). Cross- tolerance exists among opioid and to other CNS depressants as well.

Morphine produces predominantly physical dependence. It is characterized by Treatment of Ac poisoning

i. Gastric lavage with potassium permanganate to remove unabsorbed drug. It is indicated even when morphine has been injected.

ii. Respiratory support (positive pressure respiration). It also decreases pulmonary oedema formation.

iii. Maintenance of blood pressure by Iv. fluids and use of vasoconstrictors.

iv. Specific antidote is naloxone. It is given in doses of 0.4—0.8mg. i.v., repeated every 2—3 minutes till respiration picks up or till 10 mg has been administered, It is preferred because it is devoid of any agonistic actiorL and does not perse depress respiration. Since it has short duration of action, injection should be repeated every 1—4 hours later on, according to response.

Severe withdrawal syndrome which can also be precipitated by naloxone. Withdrawal of morphine in an addict will cause lacrymation, yawning, anxiety, fear, sweating, insomnia, restlessness, severe diarrhoea, mydriasis, palpitation and tremors. Delirium and convulsions are seen only occasionally. The withdrawal symptoms are probably due to rebound increase in noradrenergic and dopaminergic activity. Treatment is given in the box.

Interactions

The actions of morphine and other opioid on respiration are potentiated by phenothiazines, tricyclic antidepressants, MAO inhibitors, amphetamine and neostigmine either by retarding its metabolism or by a pharmacodynamic interaction at the level of central neurotransmitters.

• Hypotension is aggravated by antihypertensives.

• Cimetidine inhibits metabolism of morphine.

Treatment of dependence

i. Gradual withdrawal of morphine and substitution of methadone (long acting, orally effective opioid)

ii. In order to reduce the severity of withdrawal symptoms, the help of following drugs is taken: & Diazepam or chiorpromazine b. Clonidine

iii. The doses of methadone and clonidine are gradually reduced and tailed off.

iv. Naltrexone (100—200 mg on alternate days) or buprenorphine (0.4 mg three times a day sublingually) has been used to prevent relapse of addiction.

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

2. Codeine

It occurs naturally in opioid. It is methylmorphine. In the body, part of it is demethylated to morphine and is responsible for its analgesic action. It is less potent analgesic than morphine. However, it is more selective cough suppressant (only one-third as potent as morphine). It is given orally and its effect lasts for 4—6 hours after a single oral dose. Its abuse liability is low. Constipation is a prominent side effect. Codeine or its substitutes are widely used for suppressing dry, irritating cough.

3. Ethylmorphine and Pholocodeine

These drugs have codeine like actions. They are claimed to be less constipating than codeine. They have been used mainly as antitussive agents.

4. Heroin

It is diacetylmorphine (diamorphine), which is more lipid soluble. It is 3 times more potent analgesic than morphine. It has better access across the blood—brain barrier and is biotrans formed into morphine in the brain. Heroin is not used clinically being the most potent addicting drug.

5. Apomorphine

It is prepared by acid-catalyzed arrangement of morphine. It acts as potent emetic due to activation of dopaminergic receptors on the chemoreceptor trigger zone situated in the area postrema. This in turn stimulates an emetic centre located in the area of the nucleus fasciculi sediterrii. Neuroleptics like chlorpromazine block this effect. However, this effect is not blocked by antihistaminics. It produces a variety of behavioural, neuropharmacological and endocrinal effects in large doses due to its effect on both pre- and post synaptic dopamine receptors located in the neostriatum. In man, vomiting occurs promptly (with in 5 minutes)in a dose of 6 mg injected i.m/s.c. It is mainly used as experimental tool in study of psychopharmacological drugs.

6. Pethidine (Meperidine)

It is about one-tenth as potent as analgesic than morphine. However, in equianalgesic doses, it produces the same degree of respiratory depression and vomiting. Important differences from morphine are:

• Less sedative, antitussive and constipative effect.

• Shorter duration of action but onset of action is quick.

• Has atropine like actions such as spasmolytic, mydriatic and other visual effects.

• Causes less histamine release.

• Has local anaesthetic action; corneal anaesthesia is seen after systemic doses.

• Overdose of pethidine produces many excitatory effects due to accumulation of norpethidine (metabolite).

It is used as an analgesic and in preanaesthetic medication.

7. Fentanyl and Sufentanfi

They are pethidine congeners. They are more potent than morphine, both in analgesic and respiratory depression. They have shorter duration of action (30—60 min). So they are used in combination with the neuroleptic droperidol to induce neuroleptanalgesia.

Oral Transmucosal Fentanyl Citrate (OTFC) is available as a lozenge on a plastic stick (fentanyl oralet) and terms lollipop. It is used to produce conscious sedation in paediatric patients to induce relaxation and to modify the noxious stimuli of dental treatment. The principle of formulation is to permit the child to suck on the lozenge and slowly releases the active drug, fentanyl, which is absorbed across the mucous membranes of the oral cavity. The advantages of OTFC are patient’s acceptance, rapid onset and a much higher bioavailability compared with oral administration. Dose: 5— 15 j.tg/kg; doses higher than 15 pg/kg are contraindicated due to an excessive frequency of hypoventilation. The lozenge should be removed once the desired level of preoperative sedation is achieved. Respiratory depression, hypotension, itching of the eyes and nose, nausea and vomiting have been reported.

8. Methadone

It is a synthetic opioid. It is chemically dissimilar but pharmacologically very similar to morphine. It is effective orally and has a longer duration of action than morphine. It has abuse liability. Withdrawal syndrome is of gradual onset (appears after 1—2 days), prolonged and less severe. So it 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.

9. Dextropropoxyphene

It is chemically related to methadone. It has less analgesic, antitussive, respiratory depressant and addictive properties than methadone. Overdose can lead to respiratory arrest, hypotension, and cardiac arrhythmia within one hour. It is usually combined with paracetamol for use as an analgesic.

10. Ethoheptazine

It is chemically related to pethidine. It is a low efficacy orally active analgesic which is often combined with aspirin like drugs.

Points for Dental Students

1. Opioid analgesics are used in dental practice:

a. To relieve pain of terminal cancer in oral cavity

b. As preanaesthetic medication before administration of general anaesthesia

2. These are drugs of abuse. So they should be used carefully for the period during which they are indicated.

3. There are important contraindications, e.g. head injury, bronchial asthma, enlarged prostate, etc. and important drug interactions such as inhibition of morphine metabolism by cimetidine, aggravation of hypotension by antihypertensive drugs, etc.

4. So dental students must learn thoroughly all the aspects of narcotic analgesics for their safe and judicious use.

To Remember

1. Pain: Although it is an unpleasant, ill- defined subjective symptom, it is a warning signal and mainly protective in nature. It demands instant relief by drugs.

2. Analgesic is a drug that selectively relieves pain without significantly altering consciousness either by acting in the central nervous system or on peripheral pain mechanisms.

3. Opioid agonists have main affinity for mu-receptors and some affinity for kappa and delta receptors.

4. Opioid mixed agonist antagonist have agonistic activity at kappa receptors and antagonistic effect on mu-receptors. They also have affinity for sigma- receptors.

5. Opioid antagonists mainly block mu- receptors. In higher doses, they also block kappa and delta receptors.

6. a. Emetics should not be used in acute morphine poisoning because morphine depresses the vomiting centre directly. However, gastric lavage with potassium permanganate is carried out to remove unabsorbed drug even when morphine has been injected because it is excreted through bile also.

b. Morphine does not cause miosis on topical application because it occurs due to stimulation of EdingerWestphal nucleus of third cranial nerve on systemic administration.

c. Naloxone, nitrates and theophylline counteracts the effect of morphine on biliary tract completely while atropine counteracts partially.

[Source: Principles of Pharmacology for Dental Students]

About Dr. Muna

Dr. Muna Taqi is a Dental surgeon from India who has more than 10 years of experience in the field of Oral & Maxillofacial surgery, Endodontics, & Pedodontics. She has worked in multinational medical corporates in Middle East and is also a consultant dental surgeon for many. She has authored many articles for medical journals & websites and is a consultant dental expert for Healthdrip.

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