all you need to know about opioids ! Mohammad AbuAssi

Opioids Acts on opioids receptors in the CNS Mostly they have analgesic effects Opioids sometimes are Termed “narcotics” but this implies physical dependence and should be avoided as a term Morphine dose dependant agonist / naloxone antagonist The term opioid agonist-antagonist is applied to drugs such as nalbuphine which posses agonist effect at some receptors and antagonist effects at other

Opioids receptors Opioids bind to receptors distributed throughout the CNS and are the site of action of a series of endogenous polypeptides (the endrophines and enkephalins) these posses analgesic properties similar to the exogenous opioids . The enkephaliines are found in high concentrations in central grey matter of the brain stem and areas of the spinal cord , B-endorphines structurally larger molecule with a longer duration of action and is present in high concentration in the pituitary . There are large number of opioid receptors , but five have been identified : (mu)(kappa)(sigma)(delta)and(epsilon)

Pharmacokinetics and pharmactodynamics The initial distribution of opioids to the CNS is related to the degree of ionization of the drug in the blood and to the lipid solubility of the un-ionised portion Hepatic extraction of opioids is reduced during general anesthesia due to reduced hepatic blood flow and impaired hepatic clearance Active metabolites also affect the clinical action ; the most significant of these is morphine-6-glucorunate which is stronger on the meu receptors than the morphine itself Renal insufficiency

The following factors should be considered preoperatively for minimizing side effects and maintaining the dose of an opioid for intraoperative use : 1-age:increased sensitivity in the elderly 2-duration of surgery :for opioid selection 3-pulmonary disease :risk of ventilatory failure ,COPD , kyphosis .the antitussive action of opioid may impair post operative clearance of pulmonary or bronchial secretions

cont 4-endocrine abnormality :there is increased opioid sensitivity in hypothyroidism and Addison disease 5- other depressant drug 6-hepatic disease :increased sensitivity in cirrhosis and hepatitis due to decreased metabolism 7-intracranial pathology : ICP,hyperventilation 8-miscellaneuous :increased senitivity in patients with advanced malignancy or chronic infections

Morphine Its possible to synthesize morphine , Its produced commercially from the dried juices of seed capsules of the poppy Papaver somniferum. morphine is a tertiary amine and a weak base . More water soluble than most other opioids Excellent analgesic

actions May be classified as central and peripheral ;it posses both depressant and stimulant effect on the CNS

Analgesia All types of pain are relieved ,however morphine is more effective against dull and continuous pain than sharp and intermittent The pain threshold is elevated Sensation of euphoria and drowsiness which, as the dose increases progress to sleep and eventually to an anesthetic state characterized by decreased reflex irritability and profound ventilatory depression

Respiratory system Depression of ventilation occurs as a result of direct inhibition to the medullary respiratory center Both ventilatory rate and tidal volume decrease within 2-5 mins after iv injection Depression of the cough reflex

Cardiovascular effect There is little effect on arterial pressure in normal supine individuals However hypotension may occur in patient with decreased blood volume or to whom drugs with vasodilator properties(eg.phenothiazine),as morphine may cause peripheral arterial dilation as a result pf central depression of the vasomotor center ,reduction in vasoconstrictor tone and release of histamine Bradycardia may occur occasionally as a result of stimulation of vagal center

Gastrointestinal system Nausea and vomiting(persisting 6-8 hrs after administration) due to stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle ,related to dopamine like effect Morphine causes a reduce peristalsis , but INCREASED non peristaltic contractility in the GI. Gastric emptying is delayed ,and this may contribute to vomiting Absorption of orally administered drugs is impaired and constipation is common Smooth muscle contraction is increased in sphincter of oddi ,the ureter and the bladder sphincter (should be avoided in biliary and renal colic

miosis This result of the stimulation of the Edinger-Westphal nucleus of the oculomotor center Pupillary constriction may interfere with assessment of the depth of anesthesia .

Other actions Histamine release : this is responsible for the flush and sensation of warmth which follow iv injection ,and for the erythema near the site of injection , bronchospasm occurs occasionally ,so morphine shouldn’t be administered to asthmatic patient . Endocrine effects : release of ADH from the anterior pituitary and inhibition of release of ACTH,FSH and LH .these actions resemble those of endogenous opioids Metabolic :large doses of morphine may contribute to hypothermia by decreasing muscle activity and basal metabolic rate ,and by increasing heat loss through vasodilatation .

Distribution and eliminiation After iv injection 35% of morphine is bound to protein ! The reminder is distributed with a half life of 20-25 mins  Metabolism occurs mainly in the liver The elimination half life of morphine is 2-4 hrs ,however morphine-6-glucoronide is active and is present in high concentrations ,so the clinical effect of morphine may exceed that expected from the elimination half life particularly in patients with impaired renal function . Morphine crosses the placental barrier and may depress neonatal ventilation profoundly .

Dosage and administration After iv injection, analgesia reaches a peak after 15-20 mins (this must be appreciated or will result in overdose ) In a healthy adult a single bolus of 10-15mg iv , or administration of incremental doses of 2-5mg at 20 mins intervals is appropriate In the postoperative period , morphine is usually given as IM route ,in a dose of 5-20mg; the peak effect occurs 60-90 mins later The duration of action either after IV or IM is 2-4 hours ! Iv after operation (occasionally) a dose of 1-2mg per hour is usually appropriate ! *iv infusions of morphine should only be administered in the intensive care unit because of the risk of ventilatory depression Oral morphine is used in the treatment of chronic pain ,bioavailability is only 20-30% due to first pass metabolism, however morphine-6-glucorunate is higher than after IV or IM administration ! Thus oral morphine is effective in a dose of 20-40mg Morphine should be given orally in the early postoperative period as gastric emptying is impaired 

Methadone Is equipotent with morphine , but has a long elimination half life (35hrs) because of limited capacity of liver to metabolize the drug . Analgesia lasts for approximately 20 hrs !

Fentanyl It’s a synthetic opioid Its analgesic potency is approximately 100 times that of morphine Very lipid soluble, and reaches opioids receptors very rapidly ! Onset of action occur in 1-2 mins After a single dose, its duration of action is limited to 20-30 mins by redistribution, but in high doses or after infusion its effects may last for 2-5 hrs and are terminated by the elimination of the drug In elderly its actions may last up to 9 hrs !!!!

Respiratory system Large doses or infusion of fentanyl should be used only if IPPV is planned Delayed ventilatory depression may occur after a bolus iv dose , Peaks in blood concentrations are reflected rapidly by an increase in the CNS effect of fentanyl due to high lipid solubility

Cardiovascular system Little effect A small reduction in arterial pressure Heart rate may be decreased due to vagal stimulation

Other effects Sedation is relatively poor compared to morphine Nausea and vomiting as the other opioids Chest wall rigidity may occur after large doses of fentanyl ,making artificial ventilation of the lungs difficult ! Little release of histamine Spasm of sphincter of oddi

Dosage Most commonly used as analgesic during anesthesia 50-100 micrograms may be given IV to the spontaneously breathing patient Larger doses (200-800 IV) are appropriate when IPPV is used Observation in ITU for 24 hrs postoperatively

Naloxone Well tolerated and rarely cause side effects It acts within 1 min of IV injection and has duration of action approximately 30 min This relatively short duration of action may result in ventilatory depression induced by an opioid of longer duration of action . Naloxone is the only one with pure antagonist activity at all identified opioid receptors

cont In low doses , naloxone antagonizes ventilatory depression and excessive sedation without affecting pain relief ! Thus the drug should be titrated slowly against the clinical effect to avoid the emergence of excessive pain !! Analgesia produced by spinal opioids is antagonized only by large doses of naloxone ! Arterial pressure may increase after naloxone administration , this is due to the re emergence of pain or reduction of sedation 

Naloxone not effective in reversing non0opioid drugs Drug of choice for ventilatory depression in neonates Avg dose for adults (200-400 microgram), this should be administered in increments of 50-100 microgram; supplementary doses may be required after 20-30 min