Presentation on theme: "Pain Pathway and Narcotic Analgesics By Wael Hamdy Mansy, MD Assistant Professor of Pharmacology King Saud Univesity."— Presentation transcript:
Pain Pathway and Narcotic Analgesics By Wael Hamdy Mansy, MD Assistant Professor of Pharmacology King Saud Univesity
What is Pain? An unpleasant sensory and emotional experience with actual or potential tissue damage or described in terms of such damage. (International Association for the Study of Pain, 1979)
What is Pain? continued Pain of any type is the most frequent reason for physician consultation. It is a major symptom in many medical conditions, significantly interfering with a person's quality of life and general functioning. Diagnosis is based on characterizing pain in various ways, according to duration, intensity, type (dull, burning or stabbing), source, or location in body. Pain is part of the body's defense system, triggering a reflex reaction to retract from a painful stimulus, and helps to adjust behaviour to increase avoidance of harmful situations in the future.
Pain pathway Specialized receptors = free nerve endings Stimuli (Tissue Damage): –Mechanical damage –Extreme temperature –Chemical irritation Two types of neurons –A-delta fibers: for sharp pain –C- fibers: for dull pain Four distinct processes –Transduction, transmission, modulation, perception
Tissue damage Release of chemical substances and enzymes (mediators) that alter the activity and sensitivity of sensory neurons –Prostaglandins, leukotriens: sensitization of receptors –Bradykinin and PGs: stimulate the neurons directly –Histamine: pain, itching Result –increase in nociceptor activity –Hyperalgesia –Neurogenic edema
Perception Somatosensory cortex, cingulate cortex –Sensory discrimination –Emotional response fear, anxiety and panic subjective experience Reticular formation –Increased arousal –Emotional response –Somatic and autonomic motor reflexes Induction of biological and behavioural changes
1. Opioid agonists: Opioid (Narcotic) analgesic drugs 2.Mixed agonist antagonist opioids: Pentazocine, buprenorphine, butorphanol and nalbuphine. a. Alkaloids of opium: morphine, codeine, thebaine... etc b. Semisynthetic: Diacetyl morphine (Heroin) & di- hydromorphinone. c. Synthetic: meperidine, methadone, fentanyl, dextropropoxyphene.
2. Benzylisoquinoline alkaloids: Papaverine, narcotine. They have negligible C.N.S. action and spasmolytic on smooth Opium alkaloids A juice derived from the unripe capsule of Papaver Somniferum, classified into: 1. Phenanthrene alkaloids: Morphine (main constituent), codeine, thebaine. They have narcotic action, addictive, and spasmogenic on smooth muscles.
Exudate from the capsule of the opium poppy
Morphine A. Absorption 1. Well absorbed from gastrointestinal tract, nasal mucosa, lungs or sites of subcutaneous or intramuscular injection. 2. The effect of an oral dose of morphine is less than an IV dose, though the duration of action may be longer--first pass effect. Pharmacokinetics (ADME) D. Distribution 1. Concentrated in kidney, lung, liver, spleen. 2. Lower concentration in skeletal muscle, but because of mass of muscle, most of the drug in the body is in skeletal muscle. 3. Relatively small amounts cross blood-brain barrier. 4. Epidural or intrathecal administration - Long-lasting analgesia
M. Metabolism 1. Major pathway is conjugation with glucuronic acid (morphine-3-glucuronide a neuroexcitatory metabolite; morphine-6-glucuronide, an active metabolite) 2. Genetic variability (P450 system) E. Excretion 1.Major route via glomerular filtration; 90% excreted in urine in first 24 hours after administration % appears in feces, derived essentially from bile.
Morphine and related compounds act on opioid receptors which are present in C.N.S. and in peripheral tissue as gut and adrenal medulla. Endogenous opioid peptides are endorphins, enkephalins (met-enkephalin and leu-enkephalin) and dynorphins. Mechanism of action: -Part of opioid action involve release of these endogenous peptides. -These peptides may be considered as a pleasure substance and their release is increased by stress.
Opioid receptors –Countereffect to reduced cAMP : upregulation of adenylate cyclase => tolerance – are G-protein coupled receptors which inhibit adenylcyclase and cAMP – Three opioid receptor subtypes: mu (µ): account for most of the morphin effects delta ( ): mediate reduced GI motility and respiratory suppression (in addition to µ) kappa ( ): mediate dysphoria and contribute to sedation, weak analgesic effect
Mechanism of analgesic action: Spinal analgesia: Activation of presynaptic opioid receptors => decreased Ca++ flux => decreased neurotransmitter (Substance P) release => decreased transmission of pain signal from nocireceptors Supraspinal analgesia: Activation of postsynaptic opioid receptors in the medulla and midbrain => increased K+ flux => hyperpolarization => inhibition of neurons in the pain pathway.
Actions of Opioid *Ventilatory Depression is the main cause of death in opioid overdose. Sensitivity of RC to CO2 p CO2 cerebral VD CSF formation CSF pressure intra-cranial tension so avoided in head trauma, cerebral edema or brain masses. ventilatory reserve e.g. in bronchial asthma and COPD. Pass placental barrier neonatal asphyxia (due to depression of neonatal RC). Depression of Cough Center (CC) –Anti-tussive effect = treatment of dry (not productive) cough. –Codeine is non-addictive anti-tussive. –Dextromethorphan non-narcotic non-addictive anti-tussive. 1.1. Respiration 1-CNS actions
Actions of Opioid Increase threshold for pain by inhibiting both cortical and subcortical areas. Subjective reaction to pain i.e. patient’s interpretation of pain makes the patient unaware of the pain (pain may be still present, but the patient is not suffering). Relieve fear and anxiety. Best for dull aching pain more than sharp intermittent pain. 1-CNS actions 1.2. Analgesia
Due to stimulation of Edinger-Westiphal nucleus of occulomotor nerve pinpoint pupil in toxic doses. It has no effect if applied locally. Its action can be opposed by atropine. Severe respiratory depression hypoxia Mydriasis. Actions of Opioid 1-CNS actions 1.3. Miosis
Actions of Opioid 1.4. Sedation with drowsiness, inability to concentrate, mental clouding and euphoria. Euphoria contributes to addiction by persons not requiring pain relief. 1.5.Inhibit heat regulating center (HRC) hypothermia and VMC hypotension. 1.6. Stimulate Chemoreceptor trigger Zone (CTZ) vomiting and CIC bradycardia. 1-CNS actions
due to stimulation of CIC and stimulation of vagal nucleus. Actions of Opioid 2-CVS actions 2.2. Orthostatic Hypotension 2.1. Bradycardia due to inhibition of VMC & baroreceptors, bradycardia and histamine release.
3-Smooth muscles Actions of Opioid spasmogenic action: induction of smooth muscle contraction followed by incomplete relaxation 3.5. Uterus 3.2. Biliary actions 3.1. GIT Actions 3.4. Bronchi 3.3. Urinary Tract actions
Gastric, biliary and pancreatic secretions. Tone of muscles and spasm of sphincter peristaltic propulsive movement. Inhibit defecation reflex. Diphenoxylate and loperamide are anti-diarrheal opioids with no CNS effects. Actions of Opioid 3.1. GIT Actions Constipation due to
Produce spasm of wall of gall bladder and sphincter of Oddi intrabiliary pressure more pain in patients with biliary colic. Meperidine is more tolerable. Atropine partially reduces biliary spasm while opioid antagonists e.g. naloxone totally prevents it. Actions of Opioid Spasm of wall muscle and internal sphincter. ADH release. 3.2. Biliary actions 3.3. Urinary Tract actions urine retention due to
Bronchospasm due to histamine release. Actions of Opioid 3.4. Bronchi 3.5. Uterus Suppression of uterine tone prolong labor. Neonatal asphyxia (due to depression of neonatal RC), can be treated by naloxone.
Sweating, itching and wheal formation due to histamine release Actions of Opioid 4- Skin N.B. Actions of morphine can be classified into (1) Depressant actions : include analgesia, sedation. Center inhibition (RC and CC). (2) Stimulant actions : include Miosis, Constipation, Center stimulation e.g. CTZ & CIC and ADH release.
Uses of Opioid 1-Analgesic to relieve severe pain as post-operative pain, myocardial infarction, terminal cancer pain. 2-Acute left ventricular failure OR Acute pulmonary edema because it work of heart (hypotensive and venodilator effects) and relieve fear and anxiety. 3-Anesthesia : in pre-anesthetic medication (Meperidine is better) and intra-operative. 4-Cough: obsolete; codeine and dextrometorphane can be used. 5-Diarrhea: obsolete; diphenoxylate (combined with atropine Lomotil) and loperamide can be used.
Contraindications 1-Diseases with decreased respiratory reserve as bronchial asthma, COPD.. etc 2-Bilary colic. 3-Conditions with increased intracranial tension as head trauma, cerebral edema or brain masses. 4-Before diagnosis of acute abdomen 5-Extremes of Age. 6-Advanced renal or hepatic insufficiency. 7-Pregnancy and lactation.
Tolerance: Occur to analgesia, sedation euphoria and centers depression within days. No tolerance develops to miosis or constipation. Cross tolerance with other opioids and CNS depressants. Addicts can tolerate doses that normally are toxic to normal patient.
Dependence (Addiction) Both physical and psychic dependence, so sudden withdrawal abstinence syndrome or severe withdrawal symptoms include yawning, mydriasis, rhinorrhea, diarrhea, excitation, H.R., BP, aches. Withdrawal symptoms can be precipitated by opioid antagonists or mixed agonist-antagonist and improve by substituting to another opioid (cross dependence).
Treatment of opioid addiction by 1.Hospitalization and psychotherapy. 2.Gradual withdrawal of opioid until stabilizing dose, then transfer the patient from short acting opioid as morphine or heroin into a long acting oral one as methadone. 3.Gradual withdrawal of methadone. 4.Clonidine can control some withdrawal symptoms e.g. hypertension but not aches or opioid craving. 5.Opioid antagonists as naloxone (I.V.) and naltrexone (oral) can be given after complete detoxification to prevent recurrence.
Codeine (3-methoxy-morphine): – Better oral absorption than morphine – Only 20% of analgesic effect of morphine (does not increase significanly by increasing the dose) – Converted into morphine by demethylation via CYP2D6 (mutated in ~10% of the population => resistance to the analgesic effect) – CYP2D6 inhibitors (e.g. Fluoxetine) reduce efficacy of Codeine – Little euphoria => rarely addictive – Often in combination with aspirin or acetaminophen
Dextromethorphane: – Synthetic morphine derivative – Equally antitussive as codeine – Does not act through opioid receptors – No analgesic or GI effects Tramadol: 1. Codeine analog; effective for mild to moderate pain 2. Weak mu receptor agonist; also inhibits reuptake of norepinephrine and serotonin 3. Low risk of respiratory depression, tolerance, and dependence
Heroin (diamorphine): – Diacetylated morphine – Greater lipophilicity => crosses blood/brain barrier better => greater “rush”. – Excreted for the most part in urine as free and conjugated morphine. – Often combined with NSAIDs – Contained in over 200 preparations in the US – Used in slow-release formulation to treat chronic pain – People seeking an alternative to heroin often try OxyContin. They chew the time-release tablets for a quicker rush. Some crush the tablet to snort or inject it. Prescriptions are often obtained fraudulently, and in many robberies of pharmacies, only Oxycontin is stolen Hydrocodone (Vicodin®): Oxycodone (OxyContin®):
Synthetic Opioid Agonists Kinetics: Given orally or parentrally (by injection), metabolized in liver and excreted in urine. Actions: similar to morphine BUT with –Less analgesia (1/10th potency of morphine). –Less R.C. depressant. –Less addictive. –Less constipation and biliary spasm. –Atropine like action Mydriasis. 1.Meperidine:
Adverse effect: seizures (due to the metabolite noremeperidine) especially with high doses or renal insufficiency. Uses: As analgesic in biliary colic and during delivery where morphine is contraindicated. Synthetic Opioid Agonists 1.Meperidine:
Similar to morphine BUT more effective orally, less addictive with withdrawal symptoms much less than morphine. Used as long-term analgesic and in treatment of opioid addiction. Synthetic Opioid Agonists 2. Methadone :
Synthetic Opioid Agonists 3. Fentanyl : Is 80 times more potent than Morphine with shorter duration than Meperidine. It is mainly μ agonist and is used to produce neurolepto- analgesia I.V. can be given as transdermal patches for long-term management of severe pain. Alfentanil is more potent and sulfentanil is short acting
Synthetic Opioid Agonists 4. Propoxyphene : The dextro isomer has analgesic action while the levo one has anti-tussive action. Used in mild to moderate pain that not adequately controlled by Aspirin.
Opioids with Mixed Actions partial agonist on receptors and agonist on receptors. They may precipitate withdrawal symptoms in opioid addict. They have ceiling effect on respiration, i.e., respiratory depression is not proportional to analgesia. Used as analgesic mainly for moderate pain being less potent than morphine and given orally or parentrally Increase BP and HR cardiac load, so avoided as analgesic in MI. Pentazocine
Oral tablets contain a small dose of naloxone not enough to counteract the analgesic effect of pentazocine BUT when tablets are dissolved and injected I.V. (drug abuse), naloxone is now enough to counteract the pentazocine’s effect and even may precipitate withdrawal symptoms in opioid addicts. Opioids with Mixed Actions Pentazocine Nalbuphine and Butorphanol: are similar to Pentazocine but not effective orally.
Opioid Antagonists Naloxone, Naltrexone: and antagonists * In absence of opioid drugs both Naloxone and Naltrexone have no effect while nalorphine and levallorphan induce opioid actions (analgesia, miotic effect, R.C. depression with ceiling effect …….). * In acute opioid poisoning, they abolish euphoria, analgesia, miosis, vomiting, R.C. depression, gut spasm,.... * In physical dependence, they induce withdrawal symptoms.
Treatment of acute opioid poisoning and neonatal asphyxia caused by opioids, also for diagnosis of opioid addiction. Opioid Antagonists Uses:
WHO Analgesic ‘Ladder’ Severe Moderate Mild Severe Moderate Mild Step 3 Strong opioids (e.g., morphine) with or without non-opioids Step 2 Weak opioids (e.g., codeine) with or without non-opioids Step 1 Non-opioids (e.g., NSAIDs, acetaminophen = paracetamol)