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MDG5239 – Clinical Pharmacology & Pharmacotherapeutics II Opioid Analgesics Dr. David Fann [email protected] Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore, Singapore ...

MDG5239 – Clinical Pharmacology & Pharmacotherapeutics II Opioid Analgesics Dr. David Fann [email protected] Department of Pharmacology, Yong Loo Lin School of Medicine National University of Singapore, Singapore  Objectives By the end of this lecture, you will be able to: ▪ Describe and explain the major characteristics of acute and chronic pain. ▪ Describe and explain how noxious stimuli(s) are detected by the body. ▪ Describe and explain how noxious stimuli(s) are transmitted to the brain. ▪ Describe and explain the use of opioid analgesic drugs in clinical practice. for exam! ▪ Describe and explain the mechanism(s) of action, clinical indications, pharmacokinetics, adverse effects and/or contraindications of opioid analgesics and opioid antagonists.  Background: Pain What is Pain? ▪ Pain is a distressing sensory and emotional experience that is usually associated with a noxious/harmful stimuli. ▪ Pain is a subjective experience - as everyone’s threshold to pain is different due to genetics, psychology & previous experience. What may be painful to me may not be painful to you.  Background: Types of Pain I Types of Pain: ▪ In general, pain can be categorized into 2 major types: Acute Chronic develop after acute pain or a condition like neuropathic Major Clinical Characteristics of Acute and Chronic Pain: Clinical Characteristics Acute Pain Chronic Pain It can sometimes develop after acute pain. Major conditions that causes chronic pain: Musculoskeletal Conditions: e.g. Osteoarthritis, Rheumatoid Arthritis & Lower Usually linked to something specific. Back Pain. Neuropathic Pain: e.g. Diabetic Neuropathy 1). Cause - For example: Cut, Burn, Sprain, Broken Chronic Inflammatory Conditions: e.g. Bones & Surgery Inflammatory Bowel Disease – Crohn’s Disease & Ulcerative Colitis. Cancer-Related Pain: e.g. Cancer Treatment damaging nerves. Psychogenic Pain: e.g. Depression & Anxiety.  Background: Types of Pain II the differences! Major Clinical Characteristics of Acute and Chronic Pain: Continued Clinical Characteristics Acute Pain Chronic Pain 2). Onset Usually occurs suddenly. Usually occurs gradually. Usually short-lived (i.e. few minutes to weeks) Usually lasts > 3-6 months. 3). Duration It tends to resolve once the underlying cause is It may persist indefinitely, even after the treated. injury or illness is resolved. It can vary widely from mild to severe and It can vary widely from mild to severe. can fluctuate over time. 4). Intensity It usually corresponds to the extent of tissue It usually doesn’t correspond to the extent damage or injury. of tissue damage or injury. It can be localized to a specific area (e.g. Usually localized to a specific area of the body, 5). Location where the damage or injury has occurred. lower back pain or osteoarthritis) or, it can be widespread (e.g. fibromyalgia). It can vary widely. It can vary widely. It can be described as dull, aching, burning, 6). Quality It can be described as sharp, stabbing, or tingling. throbbing or aching. It may also be accompanied with numbness or stiffness.  Background: Types of Pain III Major Clinical Characteristics of Acute and Chronic Pain: Continued Clinical Characteristics Acute Pain Chronic Pain Usually accompanied by other symptoms Usually accompanied by other symptoms such such as inflammation (i.e. redness, swelling as fatigue, sleep disturbance, behavioral 7). Associated Symptoms and functional impairment of the affected changes (e.g. anxiety and depression) and area). cognitive dysfunction (e.g. “brain fog”). Usually activates the sympathetic nervous Usually changes the central nervous system 8). Physiological Response system (i.e. increased heart rate, blood making it more sensitive to pain. pressure and respiratory rate). Usually causes anxiety and depression that can Usually does NOT cause any long-term 9). Psychological Impact psychological effects. adversely affect social relationships leading to social isolation and economic hardships. Does NOT respond well to standard treatment (e.g. NSAIDS or Opioid Analgesics). Usually responds well to standard treatment Patients usually require a multidisciplinary 10). Response to Treatment (e.g. NSAIDS and/or Opioid Analgesics). approach that includes medications, physical and psychological therapy, and lifestyle changes.  Background: Nociceptors I How Does the Body Detect Noxious/Harmful Stimuli? ▪ The body is able to detect noxious/harmful stimuli through specialized receptors known as nociceptors, which are located at the ends of primary afferent sensory nerve fibers. Types of Nociceptors ▪ There are many different types of nociceptors in the body, which detect different stimuli(s) such as: Mechanical Nociceptors skin, skeletal muscles, mucous membranes joints, :by alpha-delta will cause Na+ and Ca+ sensory myelinated nerve fibres influx -> depolarization Thermal Nociceptors of activated sensory nerve fibres! Chemical Nociceptors ATP, prostaglandin, bradykinins, histamine, 5ht2, hydrogen -> by C sensory unmyelinated Polymodal Nociceptors C sensory unmyelinated nerve fibres A). Characteristic Features of Mechanical Nociceptors: physical distortion of the tissues Function: Detects mechanical damage or distortion of tissue. Stimuli: Respond to Cutting, Intense Pressure, or Stretching of Tissues. Location: Found in skin, skeletal muscles, joints, and some internal organs.  Background: Nociceptors II A). Characteristic Features of Mechanical Nociceptors: Continued alpha-delta Fiber Type: Typically associated with primary afferent A sensory nerve fibers, which are small (diameter 1-5m), myelinated nerve fibers that rapidly (3-30m/s) transmit electrical signals to the brain to produce sharp, localized pain. B). Characteristic Features of Thermal Nociceptors: Function: Detects extreme temperatures that can cause tissue damage. Stimuli: Responds to Heat (Typically > 43C; TRPV1) or Cold (Typically 8-28C; TRPM8) Temperatures. Location: Skin & Mucous Membranes Fiber Type: Typically associated with primary afferent A sensory nerve fibers, which are small (diameter 1-5m), myelinated nerve fibers that rapidly (3-30m/s) transmit electrical signals to the brain to produce sharp, localized pain. C). Characteristic Features of Chemical Nociceptors: Function: Detect chemical irritants that can cause tissue damage. Stimuli: Respond to chemicals released from tissue injury and during inflammation. For Example: ATP (Purinergic Receptors), Prostaglandins (Prostanoid Receptors), Bradykinin (Bradykinin-Type 2 chemical release during cell injury Receptors), Histamine (Histamine Receptors), 5-Hydroxytryptamine (5-HT, Serotonin) & Hydrogen ions (H+; acidosis, tissue ischemia; ASIC & TRPV1).  Background: Nociceptors III C sensory nerve fibres and unmyelinated! C). Characteristic Features of Chemical Nociceptors: Continued Location: Found in various tissues such as skin, skeletal muscles and internal organs. Fiber Type: Typically associated with primary afferent C sensory nerve fibers, which are small (diameter 0.2-1.5m), unmyelinated nerve fibers that slowly (0.5-2m/s) transmit electrical signals to the brain producing a slow, diffuse, dull, aching or burning pain. can detect 2 different stimuli, same C unmyelinated fibres D). Characteristic Features of Polymodal Nociceptors: Function: Detects multiple types of noxious stimuli. temperature & chemical stimuli Stimuli: Responds to thermal, mechanical and chemical stimuli. (e.g. TRPV1 & Capsaicin; TRPM8 & Menthol). Location: Found Widely in Skin and Deep Tissues. Fiber Type: Typically associated with primary afferent C sensory nerve fibers, which are small (diameter 0.2-1.5m), unmyelinated nerve fibers that slowly (0.5-2m/s) transmit electrical signals to the brain producing a slow, dull, diffuse, aching or burning pain.  Background: Pain How is Noxious Stimuli/Harmful Signals Transmitted to the Brain? 1). When noxious stimuli(s) activate nociceptors at the end of primary afferent Aδ or C sensory nerve fibers. 2). This will ultimately cause an influx of cations (i.e. Na+ & Ca2+) into the primary afferent Aδ or C sensory nerve fibers. 3). This will cause the cytosol to become more positive, which increases chances of the primary afferent Aδ or C sensory nerve depolarizing the activated sensory nerve fibres fibers reaching threshold. 4). This causes the primary afferent Aδ or C sensory nerve fibers to depolarize and generate an action potential, which is sent to the dorsal horn of the spinal cord. 5). The action potential then travels up the ascending contralateral spinothalamic tract in 5 Pain the spinal cord to the thalamus of the brain, where it is relayed and processed by the somatosensory cortex to provide conscious awareness of pain. goes into thalamus -> somatosensory cortex -> pain Note: Attitude, Mood or Physical Exercise can dramatically influence our perception of pain. Noxious Stimuli Nociceptors 5 Contralateral Spinothalamic 2 3 4 Dorsal Tract Pressure Histamine Primary Afferent Aδ or C Sensory Nerve Fibers Stretch Bradykinin 1 Horn back of spinal cord @ dorsal Cold Prostaglandins horn Heat 5-HT Mechanical Nociceptors ATP H+ Thermal Nociceptors Chemical Nociceptors  Pharmacological Treatments of Pain Conventional Opioid Analgesics Used to Treat Pain: Strong Opioid Analgesics: A. Morphine B. Oxycodone C. Fentanyl, Alfentanil & Remifentanil D. Pethidine (Meperidine; United States) E. Methadone Mild-Moderate Opioid Analgesics: A. Tramadol B. Codeine  Opioid Analgesics: Mechanism(s) of Action I they are agonist! they will bind onto opoid receptors and activate it ▪ Opioid analgesics bind and activate different types of opioid receptors on neurons in the brain, spinal cord and periphery to decrease or eliminate the sensation of pain in a patient. Types of Opioid Receptors 1 Opioid Analgesics releases ▪ There are 3 Major Types of Opioid Receptors: Endogenous Opioid Peptides (endorphins, enkephalins & dynorphins) Exercise or Alcohol Mu (μ)-Opioid Receptor Opioid Receptor Extracellular Inhibitory Gi-Protein Delta (δ)-Opioid Receptor Neuronal Plasma Membrane Coupled Receptors Intracellular Kappa (κ)-Opioid Receptor 2 Inhibitory Gi-Protein 3 splitting! Opioid Receptor Activation 1). When Opioid Analgesics or Endogenous Opioid Peptides bind onto Opioid Receptors, they will activate the receptor. 2). This will cause the Opioid Receptor to undergo a conformational change, which activates the inhibitory Gi-protein (Gi- protein - composed of 3 protein subunits - ,, and 𝛾. 3). When the inhibitory Gi-protein is activated, this will cause the -subunit to split away from the -and 𝛾-subunit complex. To Be Continued Note: Opioid Analgesics Primarily Induces their Analgesic Effects through the Mu (μ)-Opioid Receptors  Opioid Analgesics: Mechanism(s) of Action II i). Mechanism(s) of Action of -and 𝛾-subunit complex Opioid Analgesics +40 Membrane Potential (mV) Endogenous Opioid Peptides K+ (endorphins, enkephalins & dynorphins) 2 0 GIRK Potassium 2. Depolarization 3. Repolarization Extracellular Opioid Receptor Channels Neuronal Plasma Membrane 3 Intracellular Threshold -55 1 3 1. Initial Stimulus 4. Hyperpolarization Inhibitory Gi-Protein K+ Resting Membrane Potential -70 3 Hyperpolarization Difficulty Reaching Threshold 0 1 2 3 Difficulty for Depolarization to Occur Time (ms) ↓Generation of Action Potentials 1). The -and 𝛾-subunit complex, then binds and interacts with G-protein-coupled Inwardly Rectifying Potassium (K+) Channels (GIRKs) on the post-synaptic neuron. 2). This causes GIRK potassium channels to open, which causes an efflux of potassium ions (K+) to the extracellular environment, which makes the intracellular environment more negative causing hyperpolarization of the neuronal membrane. 3). This will make it difficult for the post-synaptic neuron to reach threshold (-55mV). Therefore, decreasing the chances of depolarization and generating an action potential.  Opioid Analgesics: Mechanism(s) of Action III ii). Mechanism(s) of Action of -and 𝛾-subunit complex Normal Opioid Analgesics Opioid Analgesics Endogenous Opioid Peptides Action Potential Action Potential (endorphins, enkephalins & dynorphins) Synaptic Voltage-Gated Synaptic Voltage-Gated Ca2+ Channel Vesicles Ca2+ Channel 1 Vesicles Extracellular Opioid Receptor Neuronal Plasma Membrane Ca2+ Ca2+ Intracellular Pre-Synaptic 2 ↓[Ca2+]I Exocytosis Terminal 3 ↓Exocytosis Inhibitory Gi-Protein Synaptic Cleft 4 Post-Synaptic Post-Synaptic Receptors Terminal Post-Synaptic Receptors 1). The -and 𝛾-subunit complex, binds and inhibits the Voltage-Gated Calcium (Ca2+) Channels in the pre-synaptic terminal. 2). This decreases the Voltage-Gated Calcium (Ca2+) Channels from opening, which decreases the influx of Ca2+ ions and ultimately the concentration of Ca2+ ions in the pre-synaptic terminal. 3). This decreases the synaptic vesicles (contains neurotransmitters) from fusing with the pre-synaptic terminal membrane, which decreases the release of neurotransmitters (i.e. exocytosis) into the synaptic cleft. 4). Therefore, less neurotransmitters will be binding onto the post-synaptic receptors to activate them, which decreases the propagation/neurotransmission of the electrical signal.  Opioid Analgesics: Mechanism(s) of Action IV each subunits that is split has a role in playing analgesia Opioid Analgesics iii). Mechanism(s) of Action of ⍺-subunit enzyme responsible Opioid Analgesics Normal ATP for conversion Endogenous Opioid Peptides inhibits Adenylate Cyclase (endorphins, enkephalins & dynorphins) Adenylate Cyclase 2nd messenger cAMP Extracellular Opioid Receptor Activates ↓[cAMP]I Neuronal Plasma Membrane Protein Kinase A Intracellular Phosphorylates ↓Protein Kinase A Activity Voltage-Gated Ca2+ Channels Inhibitory Gi-Protein in Pre-Synaptic Terminal inhibits ↓Phosphorylation of Voltage-Gated Ca 2+ Channel Adenylate Cyclase ↑Voltage-Gated Ca2+ Channel Activity ↓Voltage-Gated Ca2+ Channel Activity ↑Influx of Ca2+ Action Potential ↓Influx of Ca2+ ↑[Ca2+]I in Pre-Synaptic Terminal Synaptic ↓[Ca2+]I in Pre-Synaptic Terminal Vesicles Voltage-Gated Ca2+ Channel ↑Exocytosis of Neurotransmitters ↓Exocytosis of Neurotransmitters ↓[cAMP]I AC Pre-Synaptic ↓PKA Activity ↑Neurotransmitters Binding onto Terminal ↓[Ca2+]I ↓Neurotransmitters Binding onto Post-Synaptic Receptors ↓Exocytosis Post-Synaptic Receptors Synaptic Cleft Post-Synaptic ↑Propagation/Neurotransmission Terminal ↓Propagation/Neurotransmission of Action Potentials Post-Synaptic Receptors of Action Potentials  Opioid Analgesics: Adverse Effects I ▪ The Major Adverse Effects Associated with Opioid Analgesics are in the: all these has opiod receptors! Central Nervous System (CNS) Gastrointestinal System Immune System Cardiovascular System Musculoskeletal System Integumentary System (Skin) Respiratory System Urinary System with cardio and respi depression due to neurons unable to reach action potential in firing Central Nervous System (CNS) 1). Nausea (40%): When the patient is standing up and walking and not lying down. Due to Opioid Analgesics stimulating a chemoreceptor trigger zone (i.e. area postrema) in the medulla oblongata of the brainstem. 2). Vomiting (15%): When the patient is standing up and walking and not lying down. Due to Opioid Analgesics stimulating a chemoreceptor trigger zone (i.e. area postrema) in the medulla oblongata of the brainstem. 3). Sedation: Therefore, driving or operation of motorized vehicles should be avoided. 4). Drowsiness (i.e. Sleepiness & Lethargy): Therefore, driving or operation of motorized vehicles should be avoided. 5). Euphoria 6). Constriction of Pupils (i.e. Miosis): Due to Opioid Analgesics acting on the oculomotor nucleus in the midbrain of the brainstem, which increases parasympathetic activity. However, Mydriasis (i.e. dilatation of pupils) can occur if hypoxia occurs.  Opioid Analgesics: Adverse Effects II Central Nervous System (CNS): Continued 7). Opioid-Induced Hyperalgesia: Due to prolonged use of opioid analgesics. Paradoxically, the patient has an increased sensitivity to pain from a noxious stimuli. 8). Cardiovascular Depression: Due to Opioid Analgesics decreasing the rate of firing at the medulla oblongata (i.e. cardioregulatory nuclei) in the brain stem, which decreases heart rate (bradycardia) and consequently blood pressure. MAP = CO x TPR; CO = SV x HR. 9). Respiratory Depression: Due to Opioid Analgesics decreasing the rate of firing at the medulla oblongata in the brain stem, which decreases the rate of respiration (by decreasing both the patient’s sensitivity to CO2 and voluntary breathing). Solution: Treat with Opioid Receptor Antagonist (i.e. Naloxone). 10). Development of Tolerance: Due to long-term (days to weeks) use. Tolerance is where you have to constantly increase the dosage of the drug in order to maintain therapeutic effects. 11). Development of Dependance: This is where the Patient Experiences Physical & Psychological Withdrawal Symptoms. Due to acute cessation of treatment from long-term use or from Opioid Receptor antagonism. Solution: Opioid Analgesic should be withdrawn slowly by decreasing the dose in a step- wise fashion.  Opioid Analgesics: Adverse Effects III nitric oxide cause widespread Cardiovascular System dilation of arterioles and veins due to histamines causing vasodilation vasodilation 1). Orthostatic/Postural Hypotension: Due to Opioid Analgesics stimulating the release of histamine from mast cells. This causes histamine to bind onto H1-Receptors in endothelial cells, which stimulates the release of Nitric Oxide (NO) from endothelial cells causing the arteriolar and venous vasodilation. MAP = CO x TPR; CO = SV x HR due to hitamines Respiratory System 1). Bronchoconstriction: Due to Opioid Analgesics stimulating the release of histamine from mast cells. This causes histamine to bind onto H1-Receptors in smooth muscles causing contraction in the bronchi and bronchioles. Gastrointestinal System 1). Constipation: Due to Opioid Analgesics decreasing gastrointestinal motility (i.e. peristalsis), especially from chronic use. Musculoskeletal System 1). Increases Skeletal Muscle Tone (i.e. increases muscle stiffness): Usually Due to High Doses of Opioid Analgesics. 2). Myoclonus (i.e. sudden and brief muscular twitches or jerks): Usually Due to High Doses of Opioid Analgesics.  Opioid Analgesics: Adverse Effects IV Urinary System 1). Urinary Retention: Due to increased sphincter tone in the bladder, especially in patients with benign prostate hypertrophy. Immune System 1). Immunosuppression: Due to long-term use of Opioid Analgesics. Therefore, may increase the risk of infections. due to histamines Integumentary System 1). Urticaria (i.e. Hives/Skin Rash): Due to Opioid Analgesics stimulating the release of histamine from mast cells. This causes histamine to bind onto H1-Receptors in endothelial cells, which stimulates the release of Nitric Oxide (NO) from endothelial cells causing the arteriolar vasodilation. 2). Pruritis (i.e. Itchy Skin): Due to Opioid Analgesics stimulating the release of histamine from mast cells. This causes histamine to bind and stimulate H1-Receptors on primary afferent sensory nerve endings at the skin.  Opioid Analgesics: Caution/Contraindications ▪ The Major Caution/Contraindications Associated with Opioid Analgesics are: 1). Patients with Respiratory Diseases (e.g. Asthma, COPD): Due to Opioid Analgesics causing Respiratory Depression and Bronchoconstriction, which can worsen respiratory function. 2). Patients with Acute Hepatic Dysfunction: Due to Opioid Analgesics primarily being metabolized by the liver. 3). Patients with Severe Hepatic Diseases: Due to Opioid Analgesics primarily being metabolized by the liver. 4). Patients with Severe Renal Diseases: Due to Opioid Analgesics primarily being excreted by the kidneys. 5). Patients with Increased Intracranial Pressure: Due to Opioid Analgesics causing Respiratory Depression → Accumulation of CO2 → Dilation of Cerebrovascular Vessels → Increased Cerebral Blood Flow → Increase Intracranial Pressure. 6). Patients with Obstructive Sleep Apnea: Due to Opioid Analgesics causing Respiratory Depression, which can worsen breathing. 7). Patients with Paralytic Ileus: Paralytic Ileus is a condition where the intestines are paralyzed, and unable to move food and waste down the intestines. Opioid Analgesics can exacerbate the condition as it decreases gastrointestinal motility/peristalsis. 8). Patients with Hypersensitivity to Opioid Analgesics: Due to increased risk of allergic reactions (i.e. anaphylaxis)  Opioid Analgesics: Drug/Drug Interactions ▪ The Major Drug/Drug Interactions Associated with Opioid Analgesics are: A). Patients on other CNS Depressants (e.g. Alcohol, Benzodiazepines): Due to Opioid Analgesics increasing the risk of sedation, respiratory depression, and coma. PETHEDINE & TRAMADOL cause HTN crisis & serotonin syndrome + P450 INHIBITOR! B). Patients on Monoamine Oxidase (MAO) Inhibitors: Part 1: i). Monoamine Oxidase breaks down neurotransmitters such as noradrenaline, serotonin and dopamine in the brain. Therefore, MAO inhibitors will prevent the breakdown noradrenaline, serotonin and dopamine in the brain. Therefore, increasing their concentration. ii). Some Opioid Analgesics (especially Pethidine, Tramadol) can also increase the concentration of noradrenaline (Tramadol) or serotonin (Pethidine & Tramadol) in the brain (via blocking neuronal re-uptake). pethidine and tramadol block neuronal re-uptake, incr NA and Serotonin levels, can cause HTN crisis & serontonin syndrome iii). Therefore, combining Opioid Analgesics and MAO inhibitors can dramatically increase the concentration of noradrenaline or serotonin in the brain, which can increase the risk of life-threatening Hypertensive Crisis (Tramadol) or Serotonin Syndrome (Pethidine & Tramadol), respectively. Part 2: i). Monoamine Oxidase Inhibitors can inhibit cytochrome p450 enzymes in the liver. Therefore, decrease the breakdown of Opioid Analgesics, which can increase the concentration of Opioid Analgesics and produce acute narcotic overdose.  Pharmacological Treatments of Pain Conventional Opioid Analgesics Used to Treat Pain: Strong Opioid Analgesics: A. Morphine strong Mu, weak D & K B. Oxycodone strong Mu & short acting C. Fentanyl, Alfentanil & Remifentanil D. Pethidine (Meperidine; United States) strong Mu, safe for labour + DDI with MAOI = SS for opiod withdrawal due to long-acting 24h E. Methadone Mild-Moderate Opioid Analgesics: A. Tramadol weak Mu & 5HT, NA inhibitor- DDI with MAOI cause HTN and SS B. Codeine Weak Mu & delta  Pharmacological Treatments of Pain: Characteristics of Conventional Strong Opioid Analgesics Route(s) of Pharmacokinetic Opioid Analgesic Drug Clinical Use(s) Administration Features General Points Oral Administration: Significant First-Pass Metabolism Strong Mu (μ) Agonist Oral (includes sustained- Half-Life: ∼3-4hrs (Weaker δ & κ agonist) Widely for: release formulations) Metabolized by Liver into Provides High Analgesic 1. Morphine - Acute Pain & Injection (IV, IM or SC) active metabolite Efficacy for Severe Pain need 1st pass in liver to convert - Cancer Pain to morphine-6-glucuronide! Intrathecal active ingredient causing (morphine-6- Has High liability for -not for liver or kidney impaired! analgesic effect glucuronide) via abuse and addiction glucuronidation Excreted via Kidneys not for renal impaired patient - can offered fentanyl Oral Administration: Strong Mu (μ) Agonist Significant First-Pass (Weaker δ & κ agonist) Used for: Oral (includes sustained- Metabolism Provides High Analgesic 2. Oxycodone - Acute Pain & release formulations) Half-Life: ∼3-4.5hrs Efficacy for Severe Pain - Cancer Pain Injection (IV, IM or SC) Metabolized by the Liver Has High liability for via glucuronidation abuse and addiction Excreted via Kidneys (especially in the USA)  Pharmacological Treatments of Pain: Characteristics of Conventional Strong Opioid Analgesics Route(s) of Pharmacokinetic Opioid Analgesic Drug Clinical Use(s) General Points Administration Features for CKD or liver pts Strong Mu (μ) Agonist Provides High Analgesic Oral: Buccal, Sublingual, Highly Lipid Soluble Efficacy for Severe Pain Spray or Lozenges - easily crosses the BBB Rapid Onset (easily Used for: Topical: Transdermal - rapidly redistributes from crosses BBB) - Acute Pain (especially Post- Patch for sustained the brain → fat and Short Duration of Action 3. Fentanyl & Alfentanil Operation or Labor) & release skeletal muscles (rapidly redistributes - General Anesthesia as an Injection (IV, IM, Half-Life: ∼1-2hrs from the brain → fat and Adjuvant Intrathecal) -has many routes of admin! Metabolized by Liver skeletal muscles -cross BBB easily - rapid onset, short acting Patient Controlled Excreted via Kidneys Has High liability for Infusion Systems abuse and addiction (especially in the USA) Injection: Intravenous Strong Mu (μ) Agonist Highly Lipid Soluble Provides High Analgesic Infusions (due to short - easily crosses the BBB Efficacy duration of action) - rapidly redistributes from NOT used intraspinally Very Rapid Onset (easily Used for: the brain → fat and (i.e intrathecal or crosses BBB) 4. Remifentanil -General Anesthesia as an epidural) due to it skeletal muscles Very Short Duration of -only IV not for spine! Adjuvant Half-Life: ∼5 min Action (rapidly formulation with glycine -VERY rapid onset -cross BBB Metabolized by Plasma redistributes from the (an inhibitory Esterases (Elimination not neurotransmitter in the brain → fat and skeletal from Liver or Kidneys) muscles spinal cord)  Pharmacological Treatments of Pain: Characteristics of Conventional Strong Opioid Analgesics Route(s) of Pharmacokinetic Opioid Analgesic Drug Clinical Use(s) General Points Administration Features Used for: Strong Mu (μ) Agonist - Acute Pain (especially Oral Administration: Provides High Analgesic Labor) Significant First-Pass Efficacy for Severe Pain - Pethidine is more popular Metabolism Has Rapid Onset & over Morphine as it does Half-Life: ∼2-4hrs Intermediate Duration of not reduce uterine Metabolized by Liver into Action 5. Pethidine contractions Oral active metabolite Not used for long (Meperidine; USA) - Pethidine produces less Injection (IM, SC) (norpethidine) via N- procedures due to popular use for labour demethylation respiratory depression accumulation of Norpethidine can cause -DDI with MAOi than Morphine in the norpethidine. CNS Excitation (tremors, -rapid onset newborn. Newborn can Interacts with MAO -can be tx with Naloxone muscle twitches & be treated with Naloxone. Inhibitors causing seizures) & Hallucinations Serotonin Syndrome Strong Mu (μ) Agonist Used for: Long Half-Life: ∼>24hrs Provides High Analgesic - Cancer Pain Extensively binds and Efficacy for Severe Pain - Rehabilitation Programs accumulates in tissues Has Rapid Onset & Slow for Opioid Users Oral and slowly released 6. Methadone Benefit comes from removing Injection (IM, SC) overtime Recovery use for rehab for opiod addicts Has Long Duration of -long half life! >24h the risk of self-injection & Metabolized by Liver Action financing the drug habit Excreted via Kidneys & ↓Physical Withdrawal through crime. Bile Symptoms in Addicts  Pharmacological Treatments of Pain: Characteristics of Conventional Mild-Moderate Opioid Analgesics Route(s) of Pharmacokinetic Opioid Analgesic Drug Clinical Use(s) General Points Administration Features BP MONITORING impt as tramadol inhibit the reuptake of Noradrenaline**** Weak Mu (μ) Agonist & -NA can bind B and Alpha receptors in the systemic Serotonin (5-HT) and Noradrenaline Re-uptake Half-Life: ∼4-6hrs Inhibitor Used for: Provides Intermediate Metabolized by Liver into Mu - Acute Pain (especially Analgesic Efficacy for active metabolite (O- Post-Operation) Oral Mild/Moderate Pain 1. Tramadol - Cancer Pain Injection (IV, IM) demethylated Tramadol) Interacts with MAOi causing HTN crisis via demethylation Interacts with MAO and SS - Chronic Pain Metabolized by Liver Inhibitors causing -First pass to O demthylated Tramadol Excreted via Kidneys Hypertensive Crisis & -atypical opiod analgesics that has dual Serotonin Syndrome effect Available: Tramadol + Paracetamol Half-Life: ∼3-4hrs Weak Mu (μ) & delta (δ) Is a Pro-drug that is Agonist metabolized by Liver Provides Intermediate Mu & delta Used for: (CYP2D6) into Morphine Analgesic Efficacy for 2. Codeine - Acute Mild Pain (e.g. Oral Only ∼10% is converted Mild/Moderate Pain backache) into Morphine Used in Cough Mixtures ∼90% is Metabolized by Morphine = Anti-Tussive Liver Available: Codeine + Excreted via Kidneys Paracetamol  Opioid Antagonists: reversible, non-selective opiod receptor blockers (u, d, k) Conventional Opioid Antagonists Used in Clinical Practice: A. Naloxone: Short-Acting B. Naltrexone: Long-Acting C. Nalmefene (New): Long-Acting Clinical Indication(s) ▪ Opioid Antagonists are used to treat: Opioid Overdose (Naloxone) Opioid-Induced Respiratory Depression (Naloxone) Opioid Dependence Following Detoxification in Patients to Maintain Abstinence (Naltrexone) can bind to opoid receptors Alcohol Dependence (Naltrexone & Nalmefene): Why? Alcohol can trigger the release of endogenous opioid peptides. like exercise - release endorphins Mechanism(s) of Action ▪ Opioid Antagonists are reversible, non-selective opioid receptor blockers. They bind onto ALL (Mu (μ), Delta (δ) and Kappa (κ)) opioid receptors and prevent opioid analgesics or endogenous opioid peptides from binding onto the opioid receptors.  Opioid Antagonists: Drug Route(s) of Administration Pharmacokinetic Features General Points Blocks ALL Opioid Receptors Rapid Onset Lipid Soluble: Able to Penetrate the Moderately Short Duration of Intranasal Blood-Brain-Barrier (BBB) Action Injection: 1. Naloxone (Short-Acting) Half-Life: ∼2-4hrs Rapidly Reverses Central and - Intravenous (Usually) opioid antidote Metabolized by Liver Peripheral Opiate Effects - Intramuscular Excreted via Kidneys Used in Treating Opioid Overdose & Opioid-Induced Respiratory Depression Blocks ALL Opioid Receptors Lipid Soluble: Able to Penetrate the Rapid Onset Blood-Brain-Barrier (BBB) Long Duration of Action 2. Naltrexone (Long-Acting) Oral (Usually) Half-Life: ∼10hrs Reverses Central and Peripheral treat alcohol dependence Metabolized by Liver Opiate Effects Excreted via Kidneys Used in Treating Opioid & Alcohol Dependence Blocks ALL Opioid Receptors Intranasal Lipid Soluble: Able to Penetrate the Rapid Onset Oral Blood-Brain-Barrier (BBB) Long Duration Action 3. Nalmefene (Long-Acting) Injection: Half-Life: ∼11hrs Reverses Central and Peripheral New - Intravenous (Usually) Metabolized by Liver Opiate Effects - Intramuscular Excreted via Kidneys Used in Treating Alcohol - Subcutaneous Dependence Thank You! Questions Dr. David Fann [email protected]