Pain,opiate analgesics and antagonists Dr. Israa

Mechanism of pain and nociception Polymodal nociceptors are the main type of peripheral sensory neuron that responds to noxious stimuli; the majority are non- myelinated C fibers whose endings respond to thermal, mechanical and chemical stimuli. Chemical stimuli causing pain includes bradykinin, protons, ATP and vanilloids (e.g. Capsaicin)

Stimuli to these receptors (agonist) open cation channel s and causing membrane depolarization and AP initiation. Theses receptors are sensitized by prostaglandins which explain the analgesic effect of NSAIDs. Nociceptive fibers terminate in the superficial fibers of the dorsal horn, forming synaptic connection with transmission neurons running to the thalamus

Transmission in the dorsal horn is subjective to various modulatory influence, constituting the “gate control mechanism” Descending pathways from the midbrain and brain stem exert strong inhibitory effect on dorsal horn transmission. The descending inhibition is mediated mainly by enkephalin, 5-HT from NRM(neuclus raphi magnus) and noradrenaline which is released from the locus coeruleus.

Opioids analgesics causes analgesia partly by inhibiting transmission in the dorsal horn, partly by activating the descending pathways, partly by inhibiting excitation of the sensory nerve terminals in the periphery C-fiber activity facilitates transmission through the dorsal horn through substance P receptors and NMDA receptors.

OPIOID ANALGESICS (NARCOTIC ANALGESICS) Analgesia: Relief of pain without loss of consciousness. Opium: Natural extract from Poppy plant used for social and medicinal purpose for thousands of years to produce euphoria, analgesia, sleep and to prevent diarrhea Opioid drugs: natural + synthetic morphine-like drugs.

Opioids analgesics and antagonists Strong agonists includes: – Alfentanil – Fentanyl – Heroin – Mepridine – Methadone – Morphine – Oxycodone – Remifentanil – Sufentanil. Moderate agonists includes: – Codeine – Propoxyphene.

Mixed Agonists and Antagonists Pentazocine Nalbuphine Butorphanol Buprenorphine Opioid Antagonists Naloxone Naltrexone Nalmephine

Opioid receptors The opioid agonists act at specific receptor sites to produce their pharmacological effects. Opioid Receptors are: – μ (μ1, μ 2) – қ (қ1, қ2, қ3) – δ (δ1, δ2) They are for endogenous opioid-like substances:(which also stimulate opioid receptors) – [Met]enkephalin: Tyr-Gly-Gly-Phe-Met – [Leu]enkephalin: Tyr-Gly-Gly-Phe-Leu – Beta Endorphin: a 31 amino acid peptide with [Met]enkephalin at N-terminal sequence – Dynorphin: a 17 amino acid peptide with [Leu]enkephalin at N-terminal sequence

Endogenous Opioid Peptides (Opiopeptins) FamiliesPrecursorsPeptides Enkephalins Proenkephalins (also known as proenkephalin A) Met-enkephalin Leu-enkephalin Endorphins Pro-opiomelonocortin (POMC) MSH* ACTH* β-Lipoprotein* β-Endorphin Dynorphins Prodynorphin (also known as proenkephalin B) Dynorphin A Dynorphin B α-Neoendorphin Β-Neoendorphin * Non-opioid peptides

Opioid Receptors and their Prototypic Ligands Receptor type Representative Ligands EndogenousExogenous Mu (μ) (μ 1, μ 2 ) Β-endorphinMorphine Delta (δ) (δ 1, δ 2 ) Met-enkephalinEtorphine Kappa (κ) (κ 1, κ 2, κ 3 ) Dynorphin AEthyl-keto-cycla-zocine

Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors Drug Receptor type Mu - μKappa - κDelta - δ Agonists Morphine++++ Codeine+ Methadone+++ Meperidine++++ Fentanyl+++ Sufentanyl+++++ Partial and Mixed Agonists BuprenorphinePAAntagonist (−) PentazocinePA++ Antagonists Nalaxone and NaltrexoneAntagonist (−−−)Antagonist (−−)Antagonist (−) Endogenous Peptides Met-enkephalin+++++ Beta-endorphin+++ Dynorphin A+++++

Three genes have been identified which code for opioid peptides Beta endorphin and ACTH Enkephalins Dynorphins These neuropeptides are released by stress and appear to modulate the release of other neurotransmitters.

Mechanism of Action of opioids Morphine binds opioid receptors and thus impairs the normal sensory pathways through: – Blockade of calcium channels which leads to decreased release of substance P and glutamate from the 1 st neuron of the sensory pathway (in substantia gelatinosa in spinal cord). – Decreased c-AMP which leads to opening of K-channels and hyperpolarization of the 2 nd neuron of the sensory pathway.

Mechanism of Action of Opioids

A. Effects due to μ- receptor stimulation: Supraspinal, spinal & peripheral analgesia Euphoria Respiratory depression Miosis Decreased GIT motility, Sedation Physical dependence.. B. Effects due to қ- receptor stimulation: Spinal and peripheral analgesia, Dysphoria Sedation Respiratory depression (less) Miosis (less) Decrease GIT motility Physical dependence

C. Effects due to δ-receptor stimulation: Spinal analgesia Respiratory depression Decrease GIT motility. They are not true opioid receptors only some opioids react with them.

I. Morphine Effective orally, but is much less effective than when given parenterally due to first-pass metabolism in the liver. Metabolism involves glucuronide formation, the product of which is excreted in the urine.

A. Effects of morphine 1. Central Nervous System Effects Morphine has mixed depressant and stimulatory actions on the CNS. - Depressant effects predominate in man. - Excitatory effects predominate in cats and horses.

a) Analgesia: – Drowsiness is common – Continuous dull pain relieved more effectively than sharp intermittent pain – Most patients indicate that they can still feel the pain, but that it no longer bothers them – Morphine is an agonist at μ and қ opioid receptors.

b) Euphoria and sedation – It is mainly due to activation of μ-receptor c) Emesis – Morphine directly stimulates the chemoreceptor trigger zone, usually transient and disappear with repeated administration. d) Antianxiety e) Miosis (pinpoint pupil). – It is due to stimulation of the Edenger- Westphal nucleus of the oculomotor nerve.

f) Cough reflex is inhibited: – This action,surprisingly, does not correlate closely with analgesic and respiratory depressant effect of opiates, and its mechanism of action at receptor level is unclear – Chemical modification (Codiene and Pholcodiene ) the antitussive effect can occur at sub- analgesic dose.

g) Respiration depression: – Due to a direct effect on the brain stem respiratory center. – Death from narcotic overdose is nearly always due to respiratory arrest. – It occur at therapeutic doses but not accompanied with cardiac center depression in contrast to other CNS depressant like general anesthetic agents.

h) Other effects: – Morphine is a basic drug causes the release of histamine causes the body to feel warm and the face, nose to itch,bronchoconstriction and hypotension. – It also abolishes hunger – It dilate the cerebral vessels and increase intracranial pressure

2. Cardiovascular Effects Postural orthostatic hypotension due primarily to decreased V.M.C. activity leading to peripheral vasodilation, which may be also due in part to histamine release. In congestive heart failure, morphine decreases the left ventricular workload and myocardial oxygen demand.

3. Endocrine Effects Increases prolactin secretion Increases vasopressin (ADH) secretion (oliguria). Decreases pituitary gonadotropin (LH & FSH) secretion. Decreases stress induced ACTH secretion.

4. Gastrointestinal Effects It decrease the motility and increase the tone of the intestinal circular muscle and the tone of the anal sphincter, it also causes contraction of the gallbladder and constriction of the biliary sphincter Constipation (tolerance does not develop to this effect). Diphenoxylate and Loperamide can be used in the treatment of diarrhea. They decrease GIT motility and peristalsis

5. Genitourinary Effects Morphine prolong the second stage of labor by decreasing the strength, duration and frequency of uterine contraction Inhibit urinary bladder voiding reflex (sometimes catheterization may be required in some cases )

B. Adverse Reactions Generally direct extensions of their pharmacological actions. – Respiratory depression, apnea – Nausea and vomiting – Dizziness, orthostatic hypotension, edema – Mental clouding, drowsiness – Constipation, ileus – Biliary spasm (colic) – Dry mouth – Urine retention, urinary hesitancy – Hypersensitivity reactions (contact dermatitis, urticaria) – Immunosuppression (recurrent infections)

C. Precautions – Respiratory depression, particularly in the newborn and patients with COPD – Orthostatic hypotension – Histamine release (asthma) – Drug interactions (with other CNS depressants) – Tolerance and cross tolerance to other opioids – Benign prostatic hyperplasia(may precipitate urine retention – Dependence (psychological & physical) – Liver disease(accumulation of the drug) – Increase intracranial pressure and head injury (it enhances cerebral ischemia)

D. Therapeutic uses: - Analgesia: myocardial infarction, terminal cancer, surgery, obstetrical procedures - Dyspnea due to pulmonary edema - Severe diarrhea.

II. Other Opioid (Narcotic) Analgesics A. Heroin (diacetyl morphine) – μ- agonist – Heroin is more lipid soluble than morphine and about 2½ times more potent – It enters the CNS more readily – It is a schedule I drug and is not used clinically, but it is a drug of abuse.

B. Codeine – From opium or synthesized by methylation of morphine – Has a much better oral /parenteral absorption ratio than morphine. – Effective for mild to moderate pain, cough, diarrhea. – Metabolized in part to morphine by O-demethylation. – μ- receptor agonist. – Has a more potent histamine-releasing action than morphine. – Dependence liability of codeine is less than that of morphine,. – It is 1/12 as potent as morphine

C. Dextromethorphan: – Excellent oral antitussive – No analgesic effect – No GI effects – No respiratory depression

D. Meperidine (Pethidine) – Produces analgesia, sedation, euphoria and respiratory depression. – Less potent than morphine, mg meperidine equals 10 mg morphine. – Shorter duration of action than morphine (2-4 hrs). – Meperidine has greater excitatory activity than does morphine and toxicity may lead to convulsions. – Meperidine appears to have weak atropine-like activity. – It does not constrict the pupils to the same extent as morphine.

– Does not cause as much constipation as morphine – Purely synthetic μ- agonist – Not an effective antitussive agent. – less effect in uterine contraction commonly employed in obstetrics also causes less urine retention Adverse reactions to Meperidine – Respiratory depression – Tremors – Delirium and possible convulsions – Dry mouth – Severe reaction if given with MAOI, consists of excitement, hyperthermia and convulsions; it is due to accumulation of pethidine(norpethidine) metabolite but the details are still unclear.

E. Fentanyl – μ- agonist, related chemically to meperidine. – Approximately 80 times more potent than morphine, main use in anesthesia. – Duration of action very short (t1/2 = 20 min). – Can be given IM, IV, transdemally or via patient controlled infusion system may be given intrathecally – Often used during cardiac surgery because of its negligible effect on the myocardial contractility

F. Sufentanil – A synthetic opioid related to fentanyl. – About 7 times more potent than fentanyl. – Has a slightly more rapid onset of action than fentanyl.

G. Methadone – Pharmacology and analgesic potency similar to morphine; μ- receptor agonist. – Very effective following oral administration. – Longer duration of action than morphine due to plasma protein binding (t1/2 approximately 25 hrs). – Used in methadone maintenance programs for treatment of opioid addicts and for opiate withdrawal syndrome(it reduces the physical abstinence syndrome)make it possible to wean the addict from opioids.

H. Propoxyphene – A methadone analog. – Used orally to relieve mild to moderate pain, it is weak analgesic ;often combined with Paracetamol. – Has a low addiction potential – The most common adverse effects are: dizziness, drowsiness, and nausea and vomiting. – CNS depression is additive with other CNS depressants (alcohol and sedatives). – can cause cardio- toxicity and pulmonary edema which can not reversed by naloxone

III. Mixed Narcotic Agonists/Antagonists These drugs produce analgesia, but have a lower potential for abuse and do not produce as much respiratory depression.

A. Pentazocine – қ- agonist (analgesia) and μ-antagonist (less respiratory depression). – Orally, it has about the same analgesic potency as codeine. – Adverse reactions to Pentazocine: Nausea, vomiting, dizziness, dysphoria, nightmares and visual hallucinations. – Rarely used nowadays

B. Nalbuphine – Resembles pentazocine pharmacologically. – Like morphine, nalbuphine reduces myocardial oxygen demand. May be of value following acute myocardial infarction due to both its analgesic properties and reduced myocardial oxygen demand. – Most frequent side effect is sedation. – Less propensity to produce psychotomimetic side effects

C. Butorphanol – Resembles pentazocine pharmacologically. – 3.5 to 7 times more potent than morphine. – Not available for oral administration – They exhibit ceiling of respiratory depression effect

D. Buprenorphine – A partial agonist at μ-receptor. – 200 times more potent than morphine. – Low potential abuse, but can precipitate withdrawal in addicts – In naive persons it acts like morphine – Major use is office-based detoxification of opioids – Causes less sedation, respiratory depression and hypotension even in high doses.

IV. Opiate Antagonists Opiate antagonists have no agonist properties. They are utilized to reverse opiate induced respiratory depression and to prevent drug abuse. A. Naloxone (Narcan) – Pure opiate antagonist at all opioid receptors – Given parenterally -Short duration of action (1-4 h) – Can precipitate withdrawal in addicts.

B. Naltrexone – Oral pure opioid antagonist – Long duration of action – Contraindicated in liver disease – Used in late stages of opioid addiction treatment ( also in treatment of alcoholism). C. Nalmephine – Long-acting parenteral opioid antagonist.

Antitussives Chemical & mechanical Afferents EFFerents Stimuli Respiratory muscles Sensory receptors in upper respiratory tract Cough Center medulla

Antitussives Antitussives: against cough Coughing is a protective reflex Antitussives depress cough center, therefore depress the cough reflex. Antitussives should not be used in productive cough.

Antitussives include: 1. Opioids: – Codeine, dextromethorphan, hydrocodone, hydromorphone. – They are opioid agonists against dry cough. – They are of low abuse potential. – Side effects include: drowsiness and constipatiopn.

2. Non-opioids: – E.g. butamirate citrate which depress the cough center. 3. Peripherally acting antitussives: – These prevent irritation of sensory receptors in the upper respiratory tract. 4. Local anesthetics – also depress the cough center. They include: a)demulcents: liquorice, honey b)local anesthetics: benzonatate

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