Opioid Analgesic

Mohammad Shariful Alam (Shohan)

OPIOID ANALGESIC

Analgesics: These are the drugs, which relieves pain with or without affecting the level of consciousness. Classification of analgesic: A. Opioid analgesics or narcotics B. Non-opioid analgesics or non-narcotics. Pain: Pain is an unpleasant sensory & emotional experience associated with actual or potential tissue damage or described in terms of such damage.

 When there is tissue injury, trauma or inflammation some chemical mediators are released which induce pain such as PG, Bradykinin, Histamine etc. Types of pain: □ According to duration:  Acute pain  Chronic pain □ According to involvement of nerve fibers:  Neuropathic pain  Non-neuropathic pain. # Neuropathic pain: Pain following damage to the nervous system i.e. specific structural damage or injury to the nerve fibers; e.g. trigeminal neuralgia. Here the choice of drug is carbamazepine which relieves pain by blocking the nerve fiber Na+ channels. #Non-neuropathic pain: Due to tissue damage or inflammation or any other cause except injury to the nerve fiber. Here, Opioid and non-opioid analgesics are chosen for treatment. Development of pain includes four steps, this are1. Nociception 2. Pain perception 3. Pain reaction 4. Pain behavior.

Two components of paini. Perception of pain (reception of pain by sensory organ). ii. Emotional reaction to pain (It is the subjective feeling of pain). So, pain feeling of a person depends on the above two factors.

1

Mohammad Shariful Alam (Shohan)

Nociception: It is a consequence of tissue damage (trauma, inflammation), causing the release of chemical mediators which activates nociceptors (free nerve endings). Nociceptors are Myelinated Aδ nerve fivers → carry sharp pain  Non-myelinated C nerve fibers → carry dull pain. After nociception, pain sensation reach in the brain by- Dorsal root ganglia → Posterior horn cell → Lateral spinothalamic tract → Thalamus area 2 → Post central gyrus. Opioid: These are natural, semisynthetic or synthetic alkaloid, that pharmacologically behaves like opium and acts by occupying the opioid receptors and whose action can be antagonized by naloxone. Opioid alkaloid: Source: Papaver somniferum → unripe seed capsule → longitudinal parallel incision → Milky exudates → Dried in air → Brownish sticky mass → Powder of opium. Opium contains many (>20) alkaloids e.g., Morphine, Codeine, Thebaine, Papaverine etc, the principle one being morphine which is the prototypical opioid agonist. Codeine is synthesized commercially from morphine. [Morphine is named after Morpheus, the Greek god of dreams]

Opiate: Opiates are taken to be those opioid drugs that are derived from alkaloids of the opium poppy (papaver somniferum). Opioid receptors:

    

μ (mu) receptor [ μ1, μ2 ] κ (kappa) receptor [ κ1, κ2, κ3 ] δ (delta) receptor [ δ1, δ2 ] ε (epsilon) receptor σ (sigma) receptor.

Location of the receptors: o o o o o

Dorsal horn of spinal cord Substantia granulosa Nucleus tractus solitarious Limbic system Medial & lateral thalamus

1. Dorsal horn of spinal cord 2. Primary afferents to pain transmission neurons 3. Sub cortical regions of brain Thalamus Midbrain peri-aqueductal gray Rostral ventral medulla 4. Locus ceruleus of the brain stem

2

Mohammad Shariful Alam (Shohan)

Specific agents/Newer classification on the basis of agonist and antagonist: • Strong agonists: Morphine Hydromorphone Oxymorphone Heroin Methadone Meperidine Fentanyl (Sufentanil, Alfentanil) •

Mild to moderate agonists: Codeine Oxycodone Dihydrocodeine Loperamide

•

Mixed agonists-antagonists and partial agonists: Nalbuphine Buprenorphine Pentazocine

•

Antagonists: Naloxone Naltrexone Nalmefene [When given in the absence of an agonist drug, these antagonists are almost inert at doses that produce marked antagonism of agonist effects. When given intravenously to a morphine treated subject, the antagonist will completely reverse the opioid effects within 1-3 min.] Clinical use: i) In acute opioid overdose (Naloxone). ii) As a maintenance drug for addict in treatment programs. **Classification of narcotic/opioid analgesic: i. According to efficacy: High efficacy (for severe pain) Low efficacy (for mild to moderate pain) • Morphine  Codeine • Pethidine  Dihydrocode ine • Tramadol  Dextropropo • Methadone xyphene • Meptazinol  Pentazocine

3

• Diamorphine (Heroin) • Buprenorphine

ii.

Mohammad Shariful Alam (Shohan)

Nalbuphine



According to source: Natural ◙ Morphine ◙ Codeine ◙ Thebaine

◘ ◘ ◘ ◘ ◘ ◘

Semisynthetic Heroin (diacetyl morphine) Oxymorphine Apomorphine Hypdromorphine Hydrocodone Oxycodone

□ □ □ □ □ □ □ □

Synthetic Methadone Propoxyphene Meperidine (pethidine) Fentanyl Levorphanol Butorphanol Pentazocine Naloxone

Mechanism of action of opioids/morphine/pethidine: They act by modification of ion conductance in presynaptic and postsynaptic neuron. Their action is modulated by G protein coupled ion channels. Pre-synaptic effects ↓ Drugs bind with κ, δ, & μ receptors at pre-synaptic nerve terminal ↓ Closure of voltage gated Ca++ channel ↓ ↓ Ca++ influx ↓ Reduce release of neurotransmitters (e.g., Glutamate, Acetylcholine, Nor-epinephrine, Serotonin, Substance P)

Post-synaptic effects ↓ Drugs binds with μ receptor at postsynaptic nerve terminal ↓ ↑ K+ conductance ↓ Hyperpolarization ↓ Inhibitory postsynaptic potential (IPSP)

Inhibition of cell firing by raising the threshold for pain ↓ Decrease perception of pain ↓ Elimination of pain and subjects to tolerate pain ↓

4

Analgesic action

Mohammad Shariful Alam (Shohan)

Pharmacological effects: 1.

CNS effects:

i.

Analgesia

ii. Euphoria- Typically, patients or intravenous drug users who receive intravenous morphine experience a pleasant floating sensation with lessened anxiety and distress. iii. Sedation- The combination of morphine with other sedative-hypnotics may result in very deep sleep. iv.

Respiratory depression

v.

Cough suppression- e.g., Dextromethorphan, Codeine.

vi. Miosis- Morphine binds with receptor in Edinger Westphill nucleus and thereby causes constriction of pupil. vii.

Truncal rigidity

viii.

Nausea & vomiting- Activate the brainstem chemoreceptor trigger zone to produce nausea and vomiting. Hyperthermia

ix. 2.

Peripheral effects:

a.

Cardiovascular system• Bradycardia, except pethidine which causes tachycardia, due to its antimuscarinic action. • Hypotension by releasing histamine. (→ Vasodilatation → ↓ PR→ ↓ HR)

b.

Gastrointestinal tract• Stomach motility (rhythmic contraction and relaxation) may decrease but tone (persistent contraction) may increase- particularly in central portion.

• • •

Gastric secretion of hydrochloric acid is decreased. Small intestine resting tone is increased, with periodic spasms. In large intestine, propulsive peristaltic waves are diminished and tone is increased; this delays passage of the fecal mass and allows increase absorption of water, which leads to constipation.

5

c.

• •

• •

Biliary tractMohammad Shariful Alam Constrict biliary smooth muscle resulting in biliary colic. (Shohan) Constrict sphincter of Oddi resulting reflux of biliary and pancreatic secretion and elevated plasma amylase and lipase level. d. Renal↓ Renal blood flow Anti-diuretic effects

•

↑ Urethral & bladder tone & ↑ sphincter tone, leading to urinary retention.

e.

UterusReduce uterine tone and prolong labor.

f. •

NeuroendocrineStimulate the release of ADH, prolactin, and somatotropin.

•

Inhibit the release of luteinizing hormone.

•

g.

Pruritus• Flushing and warming of the skin • Sometimes sweating and itching

due to release of histamine

h.

Miscellaneous• Modulate the immune system by effects on lymphocytes proliferation, antibody production, and chemotaxis. **Indication of morphine/opioids: i. As analgesic for-

       ii. iii. iv. v. vi.

Visceral pain (e.g., acute MI) Pain of terminal illness Cancer pain Post operative pain Obstructed labour (Pethidine) Pericarditis Pleurisy Acute LVF Control of cough (Dextromethorphan, Codeine) As anti-diarrhoeal (Diphenoxylate, Loperamide) Pre-anesthetic medication As constipating agent after colostomy.

Q. Why pethidine is chosen for obstetric pain but not morphine? 1) Pethidine does not delay labor as it has no inhibitory action on uterine musculature.

6

2) Morphine undergoes glucoronidation for metabolism and excretion. But placenta lacks glucoronyl transferase enzyme. So, morphine is not metabolized in placenta. Besides, Mohammad Shariful Alam (Shohan) Pethidine is metabolized in the placenta by alkylation. 3) Pethidine has short duration of action; as a result respiratory depression of foetus will not be prolonged. Q. Write down the sign symptoms of morphine poisoning. How will you treat a case of morphine poisoning? Ans. On the basis of actions on the C.N.S. the signs can be divided into following three stagesA. Stage of excitement 1.↑ Sense of wellbeing. 2.↑ Mental activity. 3.Freedom from anxiety. 4.Talkativeness. 5.Restlessness or even hallucination. 6.Flushing of the face. 7.Maniacal condition. 8.↑ HR.  In case of children convulsion may occur.

B. Stage of stupor 1. Headache . 2. Nausea, vomiting 3. Incapacit y for exertion. 4. A sense of weight in the limbs. 5. Giddiness & drowsiness. 6. An uncontrollable desire to sleep from which pt. can be aroused by painful stimuli. 7. Pupils are contracted. 8. Face & lips are cyanosed. 9. An itching sensation felt all over the skin. 10. Pulse & respiration are almost normal.

C. Stage of narcosis 1. Pt. passes into deep coma from which the pt. cannot be aroused. 2. Muscles are relaxed. 3. Reflexes are abolished. 4. Pin pointed pupil- not reacting to light. 5. ↓ BP. 6. Pulse- rapid & feeble. 7. Breathing is slow, gradually diminished in rate. 8. Cold clammy skin & temp – subnormal. 9. All the secretions are suppressed except sweating. 10. Death may occur from asphyxia.

Treatment:

1. Stomach wash with warm water & then KMnO4. 2. Naloxone: Specific opioid antagonist 2 mg IV. Repeated administration after 20-60 min. Total dose is 10-20 mg. 3. Nalorphine: Specific antidote for morphine. 7

4. 5. 6. 7. 8. 9.

5-10 mg is given I/V until respiration returns to normal & the pt. is aroused, 4 hourly. Maximum dose: 40 mg. Patient should be kept awake. For respiratory resuscitation: O2 inhalation. For cardiovascular resuscitation: 5% DA 1000 ml (warm). Maintenance of body temperature- by hot bottle, blanket. Close monitoring of the pt. – pulse, BP, respiration. Mohammad Shariful Alam Other symptomatic treatment(Shohan) • Antibiotics to prevent pulmonary infection. • Correction of fluid and electrolyte imbalance.

Q. How does morphine differ from pethidine? Ans. Traits 1. Source 2. Analgesic potency 3. Duration of analgesia 4. Onset of action 5. Cough suppression 6. Hypnotic action 7. Effect on labor 8. Atropine like side effects 9. Histamine release 10. Tolerance 11. Urinary retention 12. Effect on eye

Morphine Natural- opium 10 times more potent 4-6 hours Late Marked Marked Cannot be used as it delays labor Absent Occurs Develops quickly May occur Pin pointed pupil

Pethidine Synthetic Less potent 2-3 hours Immediate Less Less Can be used Present Large dose shows antihistamine action Slowly Doesn’t occur Dilatation of pupil

**Q. What are the advantages of pethidine over morphine? Ans. Advantages of pethidine over morphine arei. Immediate onset of action ii. Shorter duration of action (2-4 hours) iii. Less hypnotic effect iv. Relatively less respiratory depression v. Used in delivery because it does not delay labour

8

vi. Shows antihistamine action vii. Does not cause urinary retention viii.Less tolerance ix. Less addiction liability. Mohammad Shariful Alam (Shohan)

Q. How does pethidine differ from paracetamol? Ans. Pethidine Opioid analgesic Relieve pain by acting on CNS

Paracetamol Non-opioid analgesic Relieve pain by peripheral mechanism or enzyme mechanism Highly potent Less potent Produce narcosis No narcosis Acts via activation of endogenous opioid Acts by inhibiting prostaglandin synthesis receptors No anti-inflammatory and anti-pyretic Have anti-inflammatory & anti-pyretic effect action Low therapeutic index High therapeutic index Addicting Non addicting Tolerance and dependency can develop No such effect with paracetamol Used in visceral pain Used in somatic pain Adverse effects of opioid analgesics:

A. Direct toxic effect of the opioid analgesics that are extension of their acute pharmacological actions include• Behavioral restlessness, tremulousness, hyperactivity • ↑ Intracranial pressure (ICP) • Respiratory depression • Nausea & vomiting. • Constipation & urine retention • Miosis • Postural hypotension accentuated by hypovolumia. • Urticaria and itching around the nose (in i/v administration) B. Tolerance and dependence. Tolerance:

9

With frequently repeated administration of therapeutic doses of morphine or its surrogates, there is a gradual loss of effectiveness, is called tolerance. Although development of tolerance begins with the first dose of opioid, tolerance Mohammad Shariful Alam (Shohan) does not become clinically manifest until after 2-3 weeks of frequent exposure to ordinary therapeutic doses. Tolerance develops most readily when large doses are given at short interval. Physiological dependence: It is defined as the occurrence of a characteristic withdrawal or abstinence syndrome when the drug is stopped or an antagonist is administered. Sign symptom of physiological dependence/opioid withdrawal:           

Rhinorrhea Lacrimation Chills Hyperventilation Hyperthermia Mydriasis Muscular aches Vomiting Diarrhoea Anxiety Hostility (i.e. person suddenly becomes furious).

Administration of an opioid at this time suppresses abstinence signs and symptoms almost immediately. Mechanism of development of tolerance and physiological dependence: It is actually not known but there is an assumption that these conditions due to a cellular adaptive response that is associated with changes in second messenger systems related to Ca++ flux, adenyl cyclase inhibition and protein phosphorylation. Chronic exposure and tolerance to opioids is associated with an elevation of intracellular Ca++ content. The effects appear to be related to a change in the receptor ability to associate with G-coupling proteins, increased amounts of G-proteins and an unregulated cAMP system. In addition the number of receptors may be reduced by internalization and by reduced synthesis. Or, Continuous exposure to morphine ↓

10

↓ Ca++ influx ↓ ↓ NT release

(+) adenyl cyclase ↓ ↑ cAMP production

(-) Endogenous opioid production Mohammad Shariful Alam (Shohan)

Q. Name the endogenous opioids. Ans. Endogenous opioids:  Endorphin  Encephalin  Dynorphine. Withdrawal syndrome: When an addict misses his first shot, he feels sense of some psychological as well as physiological unusual, unpleasant and excessive effect which gradually rises & reaches its peak within 48-72 hours, gradually subsiding thereafter for the 5-10 days. Opioid withdraw ↓

↑ NT release

Acute opioid deficiency

Opposite action of opioid

Psychological dependence: It is a state characterized by euphoria, indifference to stimuli and sedation usually caused by the opioid analgesics, especially when injected intravenously.

Contraindication: • • • • • • •

Use of pure agonists with mixed-antagonist Use in patients with head injury Use during pregnancy Use in patients with impaired pulmonary function. Use in patients with impaired hepatic and renal function Use in patients with endocrine disease Acute abdomen until diagnosis

11

• •

Habitual constipation Children & infant.

Mohammad Shariful Alam (Shohan)

Q. Why morphine is contraindicated in head injury? Ans. If opioids are administered in head injury the condition is aggravated. i.

Morphine ↓ Causes respiratory depression ↓ CO2 retention ↓ Cerebral vasodilatation ↓ ↓ Cerebral vascular resistance ↓ ↑ Cerebral blood flow ↓ ↑ Intracranial pressure (ICP) ↓ Alteration of brain function

ii.

Opioids cause miosis and vomiting which are the grave sign symptoms of head injury.

iii.

Besides, by acting on spinal cord it may initiate epileptic convulsion. So administration of opioids may interfere with the diagnosis of head injury.

Drug interactions:  Opioids + Sedative hypnotics: Increased CNS depression, particularly respiratory depression.  Opioids + Antipsychotic tranquilizers: Increased sedation and accentuation of CVS effects (antimuscarinic and alpha blocking action).  Opioids + MAO inhibitors: Relative contraindication to all opioid analgesics because of the high incidence of hyperpyrexic coma. Hypertension can also be reported.

12