Assistant Professor of Pharmacology 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. 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. Diagnosis is based on characterizing pain in various ways, according to duration, intensity, type (dull, burning or stabbing), source, or location in body.

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

Normal Pain Pathways Stimulus cortex thalamus lateral spino- thalamic tract dorsal root ganglion Stimulus

Sensory Receptor Types

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 Somatic and autonomic motor reflexes Induction of biological and behavioural changes

Pain Modulation

Opioid (Narcotic) analgesic drugs 1. Opioid agonists: a. Alkaloids of opium: morphine, codeine, thebaine ... etc b. Semisynthetic: Diacetyl morphine (Heroin) & di-hydromorphinone. c. Synthetic: meperidine, methadone, fentanyl, dextropropoxyphene. 2.Mixed agonist antagonist opioids: Pentazocine, buprenorphine, butorphanol and nalbuphine.

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. 2. Benzylisoquinoline alkaloids: Papaverine, narcotine. They have negligible C.N.S. action and spasmolytic on smooth

Exudate from the capsule of the opium poppy

Morphine Pharmacokinetics (ADME) 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. 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 Major route via glomerular filtration; 90% excreted in urine in first 24 hours after administration 2. 7-10% appears in feces, derived essentially from bile.

Mechanism of action: • 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. -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 – are G-protein coupled receptors which inhibit adenylcyclase and  cAMP –Countereffect to reduced cAMP : upregulation of adenylate cyclase => tolerance – 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 1-CNS actions 1.1. Respiration *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.

Actions of Opioid 1-CNS actions 1.2. Analgesia 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.

Actions of Opioid 1-CNS actions 1.3. Miosis 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 1.4. 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.

2.2. Orthostatic Hypotension Actions of Opioid 2-CVS actions 2.1. Bradycardia due to stimulation of CIC and stimulation of vagal nucleus. 2.2. Orthostatic Hypotension due to inhibition of VMC & baroreceptors, bradycardia and histamine release.

Actions of Opioid 3-Smooth muscles spasmogenic action: induction of smooth muscle contraction followed by incomplete relaxation 3.1. GIT Actions 3.2. Biliary actions 3.3. Urinary Tract actions 3.4. Bronchi 3.5. Uterus

Actions of Opioid 3.1. GIT Actions Constipation due to  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 3.2. Biliary actions 3.3. Urinary Tract actions 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. 3.3. Urinary Tract actions urine retention due to Spasm of wall muscle and internal sphincter.  ADH release.

Suppression of uterine tone  prolong labor. Actions of Opioid 3.4. Bronchi Bronchospasm due to histamine release. 3.5. Uterus Suppression of uterine tone  prolong labor. Neonatal asphyxia (due to depression of neonatal RC), can be treated by naloxone.

Actions of Opioid 4- Skin Sweating, itching and wheal formation due to histamine release 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.

Adverse effects Gut upset. respiratory depression. constipation. increased biliary Pressure. urine retention. Hypotension.

Tolerance: Occur to analgesia, sedation euphoria and centers depression within 10-14 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 Hospitalization and psychotherapy. 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. Gradual withdrawal of methadone. Clonidine can control some withdrawal symptoms e.g. hypertension but not aches or opioid craving. 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: Tramadol: – 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. Hydrocodone (Vicodin®): – Often combined with NSAIDs – Contained in over 200 preparations in the US Oxycodone (OxyContin®): – 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

Synthetic Opioid Agonists Meperidine: 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.

Synthetic Opioid Agonists 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 2. Methadone : 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 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 Pentazocine 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.

Opioids with Mixed Actions 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. 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.

Opioid Antagonists Uses: Treatment of acute opioid poisoning and neonatal asphyxia caused by opioids, also for diagnosis of opioid addiction.

WHO Analgesic ‘Ladder’ 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)

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