Opioid Analgesics

Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Known for their remarkable efficacy, opioids induce their effects ( analgesia Analgesia Methods of pain relief that may be used with or in place of analgesics. Anesthesiology: History and Basic Concepts, euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy, and sedation) by interacting with opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (μ, κ, and δ) in the nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. Nervous System: Anatomy, Structure, and Classification. Opiates/opioids have adverse effects that include respiratory depression, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, decreased GI motility Motility The motor activity of the gastrointestinal tract. Gastrointestinal Motility and constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, tolerance Tolerance Pharmacokinetics and Pharmacodynamics, dependence, and addiction Addiction Substance use disorders are a significant cause of morbidity and mortality, especially among adolescents and young adults. A substance-related and addictive disorder is the continued use of a substance despite harmful consequences; these include significant impairment to one's health or relationships or failure to fulfill major responsibilities at work, school, or home because of substance use. Substance-Related and Addictive Disorders.

Last updated: May 30, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Pharmacodynamics

Definitions

Opioids are a class of natural or synthetic drugs that act on opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors to provide analgesia Analgesia Methods of pain relief that may be used with or in place of analgesics. Anesthesiology: History and Basic Concepts and CNS effects.

  • Opiates: a subclass of opioids, consisting of alkaloid drugs derived naturally from the opium poppy
  • Endorphins Endorphins One of the three major groups of endogenous opioid peptides. They are large peptides derived from the pro-opiomelanocortin precursor. The known members of this group are alpha-, beta-, and gamma-endorphin. The term endorphin is also sometimes used to refer to all opioid peptides, but the narrower sense is used here; opioid peptides is used for the broader group. Receptors and Neurotransmitters of the CNS: endogenous peptides that provide pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways relief by binding to opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
    • Beta-endorphins
    • Dynorphins Dynorphins A class of opioid peptides including dynorphin a, dynorphin b, and smaller fragments of these peptides. Dynorphins prefer kappa-opioid receptors and have been shown to play a role as central nervous system transmitters. Receptors and Neurotransmitters of the CNS
    • Enkephalins Enkephalins One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. Receptors and Neurotransmitters of the CNS

Mechanism of action

  • There are 3 classical opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors located in the central and peripheral nervous systems:
    • Mu
    • Kappa
    • Delta
  • Effect on opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
    • Activation of opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → stimulation of coupled G-proteins 
    • Synaptic transmission Synaptic transmission The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors, activating them. The activated receptors modulate specific ion channels and/or second-messenger systems in the postsynaptic cell. In electrical synaptic transmission, electrical signals are communicated as an ionic current flow across electrical synapses. Synapses and Neurotransmission → inhibit pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways signals:
      • Close presynaptic calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes channels Channels The Cell: Cell Membrane → ↓ neurotransmitter release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology
      • Open postsynaptic potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia channels Channels The Cell: Cell Membrane → outward movement of K → hyperpolarization Hyperpolarization Membrane Potential → ↓ neuronal excitability Excitability Skeletal Muscle Contraction
  • Opioids can be:
    • Agonists
    • Partial agonists: have ↑ receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors affinity, but ↓ receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors efficacy
    • Agonist-antagonists: may have agonist and antagonist effects at different opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

The following table summarizes and compares the effects of opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:

Table: Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors subtypes
Mu (μ) receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors Kappa (κ) receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors Delta (δ) receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
Effect on analgesia Analgesia Methods of pain relief that may be used with or in place of analgesics. Anesthesiology: History and Basic Concepts Spinal and central Spinal Spinal
Effect on GI tract Slowed gastric transit
Other effects
  • Respiratory depression
  • Euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy
  • Sedation
  • Miosis Miosis Pupil: Physiology and Abnormalities
  • Modulation of hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types
  • Dysphoria
  • Sedation
  • Diuresis
  • Anxiolysis
  • Hormone changes
Habituation None None Tolerance Tolerance Pharmacokinetics and Pharmacodynamics
Agonists
  • Beta-endorphins
  • Morphine
  • Fentanyl
  • Dynorphins Dynorphins A class of opioid peptides including dynorphin a, dynorphin b, and smaller fragments of these peptides. Dynorphins prefer kappa-opioid receptors and have been shown to play a role as central nervous system transmitters. Receptors and Neurotransmitters of the CNS
  • Mixed-action agonists
  • Enkephalins Enkephalins One of the three major families of endogenous opioid peptides. The enkephalins are pentapeptides that are widespread in the central and peripheral nervous systems and in the adrenal medulla. Receptors and Neurotransmitters of the CNS
  • Morphine
  • Codeine

Physiology effects

CNS: 

  • Analgesia Analgesia Methods of pain relief that may be used with or in place of analgesics. Anesthesiology: History and Basic Concepts
  • Euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy
  • Dysphoria
  • Sedation
  • Respiratory depression 
  • Bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias
  • Cough suppression Suppression Defense Mechanisms
  • Miosis Miosis Pupil: Physiology and Abnormalities
  • Truncal rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon
  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Tolerance Tolerance Pharmacokinetics and Pharmacodynamics
  • Opioid-induced hyperalgesia Hyperalgesia An increased sensation of pain or discomfort produced by minimally noxious stimuli due to damage to soft tissue containing nociceptors or injury to a peripheral nerve. Pain: Types and Pathways 
  • Opioid-induced allodynia Allodynia Pain due to a stimulus that does not typically provoke pain. Pain Management

Peripheral:

  • ↓ GI motility Motility The motor activity of the gastrointestinal tract. Gastrointestinal Motility constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Contraction of biliary smooth muscle → biliary colic
  • Renal plasma flow Renal plasma flow The amount of plasma that perfuses the kidneys per unit time, approximately 10% greater than effective renal plasma flow. It should be differentiated from the renal blood flow; (RBF), which refers to the total volume of blood flowing through the renal vasculature, while the renal plasma flow refers to the rate of plasma flow. Glomerular Filtration → ↓ renal function
  • Prolongation of labor Labor Labor is the normal physiologic process defined as uterine contractions resulting in dilatation and effacement of the cervix, which culminates in expulsion of the fetus and the products of conception. Normal and Abnormal Labor
  • Secretion Secretion Coagulation Studies of: 
    • Antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia (ADH)
    • Prolactin Prolactin A lactogenic hormone secreted by the adenohypophysis. It is a polypeptide of approximately 23 kd. Besides its major action on lactation, in some species prolactin exerts effects on reproduction, maternal behavior, fat metabolism, immunomodulation and osmoregulation. Breasts: Anatomy
    • Somatotropin 
  • Flushing
  • Sweating
  • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives)
Effects of opioid analgesics in relation to the strength of the drug

Effects of opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation analgesics in relation to the strength of the drug

Image by Lecturio. License: CC BY-NC-SA 4.0

Pharmacokinetics

Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

  • Can be given in parenteral, oral, nasal insufflation, and transdermal preparations
  • Most are well absorbed

Distribution

  • Protein binding varies
  • Localize in highly perfused tissues:
    • Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification
    • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy
    • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy
    • Spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy
  • Accumulation can occur in:
    • Skeletal muscle
    • Fatty tissue

Metabolism and excretion

  • Significant and variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables 1st-pass metabolism
  • Most opioids are metabolized by:
  • Excretion: renal

Classification

Action on receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

The opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation analgesics can be classified on the basis of their activity on opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:

  • Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation agonists:
    • Strong agonists:
      • Fentanyl
      • Hydromorphone
      • Levorphanol
      • Meperidine
      • Methadone
      • Morphine
      • Oxymorphone
    • Moderate agonists:
    • Weak agonists: propoxyphene
  • Agonist–antagonist: 
    • Nalbuphine
    • Buprenorphine

Origin

Opioids can be characterized as:

  • Natural (opiates):
    • Morphine
    • Codeine
  • Semisynthetic opioids:
    • Heroin Heroin A narcotic analgesic that may be habit-forming. It is a controlled substance (opium derivative) listed in the U.S. Code of federal regulations, title 21 parts 329. 1, 1308. 11 (1987). Sale is forbidden in the United States by federal statute. Nephrotic Syndrome
    • Oxycodone
    • Hydrocodone Hydrocodone Narcotic analgesic related to codeine, but more potent and more addicting by weight. It is used also as cough suppressant. Neonatal Abstinence Syndrome
    • Hydromorphone
    • Oxymorphone
  • Synthetic opioids:
    • Fentanyl
    • Methadone
    • Tramadol

Indications

Indications and uses

  • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways:
    • Moderate to severe nociceptive pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways:
      • Surgical
      • Tumor-related pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
      • Sickle cell crisis
    • Acute MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
    • Generally, opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation therapy is indicated only after more conservative analgesic measures have failed.
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea (particularly in end-of-life care)
  • Cough (codeine)
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea ( loperamide Loperamide One of the long-acting synthetic antidiarrheals; it is not significantly absorbed from the gut, and has no effect on the adrenergic system or central nervous system, but may antagonize histamine and interfere with acetylcholine release locally. Antidiarrheal Drugs)
  • Anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts before surgery 
  • Perioperative shivering Shivering Involuntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals. Body Temperature Regulation

The following table summarizes the stepwise approach recommended for treating pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways:

Table: WHO ladder governing analgesics
Step Recommended therapy
1 Nonopioid analgesics
2 Nonopioid analgesics + mild opioids (tramadol)
3 Nonopioid analgesics + strong opioids (morphine, hydromorphone, and oxycodone)
4 Invasive techniques such as epidural injection, peripheral local anesthesia Anesthesia A state characterized by loss of feeling or sensation. This depression of nerve function is usually the result of pharmacologic action and is induced to allow performance of surgery or other painful procedures. Anesthesiology: History and Basic Concepts, and ganglion block

Equianalgesic dosing

  • Helpful when converting from one opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation to another
  • Helps avoid iatrogenic Iatrogenic Any adverse condition in a patient occurring as the result of treatment by a physician, surgeon, or other health professional, especially infections acquired by a patient during the course of treatment. Anterior Cord Syndrome underdosing/overdosing
  • Morphine is the gold standard comparator for equianalgesic dosing.
  • Dosing of other opioids can be based on their relative potency compared to morphine:
    • Referred to as morphine milligram equivalents (MME)
    • Expressed as a ratio: (drug X)/(1 MME)
      • Example: 1 mg of morphine has analgesic efficacy equal to 1 mg of hydrocodone Hydrocodone Narcotic analgesic related to codeine, but more potent and more addicting by weight. It is used also as cough suppressant. Neonatal Abstinence Syndrome, so hydrocodone Hydrocodone Narcotic analgesic related to codeine, but more potent and more addicting by weight. It is used also as cough suppressant. Neonatal Abstinence Syndrome = 1/1 MME
      • Example: 4 mg of morphine has analgesic efficacy equal to 1 mg of hydromorphone, so hydromorphone = 4/1 MME
      • Example: 1 mg of morphine has analgesic efficacy equal to 6.6 mg of codeine, so codeine = 0.15 MME
  • Special consideration should be given when converting between IV and oral opiates/opioids:
    • Generally, IV opioids are 3 times more potent than their oral analogues.
    • Example: 3 mg of oral morphine has analgesic potency equal to 1 mg of IV morphine.
Table: Calculating morphine milligram equivalents (MME)*
Drug MME
Codeine 0.15
Fentanyl transdermal (in mcg/hr) 2.4
Hydrocodone Hydrocodone Narcotic analgesic related to codeine, but more potent and more addicting by weight. It is used also as cough suppressant. Neonatal Abstinence Syndrome 1
Hydromorphone 4
Methadone:
  • 1–20 mg/day
  • 21–40 mg/day
  • 41–60 mg/day
  • ≥ 61–80 mg/day
  • 4
  • 8
  • 10
  • 12
Morphine 1
Oxycodone 1.5
Oxymorphone 3
*These dose conversions are estimated and cannot account for all individual differences in genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics and pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics.

Adverse Effects and Contraindications

Adverse effects

  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema)
  • Respiratory depression
  • CNS depression
  • Bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Lowered seizure threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction (particularly with tramadol)
  • QT prolongation (particularly with methadone)
  • Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation abuse and dependence
  • Opioid-induced hyperalgesia Hyperalgesia An increased sensation of pain or discomfort produced by minimally noxious stimuli due to damage to soft tissue containing nociceptors or injury to a peripheral nerve. Pain: Types and Pathways
  • Opioid-induced allodynia Allodynia Pain due to a stimulus that does not typically provoke pain. Pain Management

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

Absolute:

  • Acute head injuries
  • Pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care
  • Impaired pulmonary function
  • Adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison’s Disease (Addison’s disease) 
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto’s disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism ( myxedema Myxedema A condition characterized by a dry, waxy type of swelling (edema) with abnormal deposits of mucopolysaccharides in the skin and other tissues. It is caused by a deficiency of thyroid hormones. The skin becomes puffy around the eyes and on the cheeks. The face is dull and expressionless with thickened nose and lips. Edema
  • Previous drug and/or alcohol rehabilitation 
  • Family or personal history of substance abuse

Relative:

  • Children < 1 year of age
  • History of depression or anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
  • Respiratory insufficiency (e.g., chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD))
  • Increased intracranial pressure Intracranial Pressure Idiopathic Intracranial Hypertension
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension or hypovolemia Hypovolemia Sepsis in Children due to the BP-lowering effects
  • Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation dependence

Use with caution:

  • Hepatic impairment
  • Renal impairment

Drug interactions

  • CNS depressants (compound risk of sedation and life-threatening respiratory depression): 
    • Hypnotics
    • Phenothiazines
    • Tranquilizers
    • Alcohol
  • Drugs metabolized by P450 systems
  • QT-prolonging agents (with methadone)
  • Serotonergic agents (with tramadol, meperidine) → serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome
  • Monoamine oxidase Oxidase Neisseria (MAO) inhibitors (with meperidine) → hyperpyrexia syndrome
  • Variability exists with individual agents.

Tolerance Tolerance Pharmacokinetics and Pharmacodynamics and physical dependence

  • Tolerance Tolerance Pharmacokinetics and Pharmacodynamics:
    • A gradual loss in effectiveness with therapeutic doses
    • Need for progressive dose escalations to achieve previous levels of analgesia Analgesia Methods of pain relief that may be used with or in place of analgesics. Anesthesiology: History and Basic Concepts, euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).
    • Reflects change in opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors density and receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors physiology after prolonged and/or repeated agonist exposure 
  • Dependence:
    • Phenomenon of drug withdrawal symptoms triggered by cessation of dose deescalation:
      • Muscle aches
      • Restlessness
      • Anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
      • Lacrimation
      • Rhinorrhea Rhinorrhea Excess nasal drainage. Respiratory Syncytial Virus
      • Diaphoresis
      • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
      • Frequent yawning
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
      • Abdominal cramping Abdominal cramping Norovirus
      • Piloerection
      • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
      • Mydriasis Mydriasis Dilation of pupils to greater than 6 mm combined with failure of the pupils to constrict when stimulated with light. This condition may occur due to injury of the pupillary fibers in the oculomotor nerve, in acute angle-closure glaucoma, and in adie syndrome. Glaucoma
      • Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
      • Hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Thought to be due to persistent activation of mu receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors

Opioid Antagonists

The following table compares the most common opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation antagonists:

Table: Comparison of the most common opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation antagonists
Medication Mechanism Indication Side effects
Naloxone Mu: competitive antagonist
  • Emergent reversal from opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation overdose
  • Reduces sedation and respiratory depression
Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation withdrawal
Naltrexone Competitive antagonist at mu, kappa, and delta receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Opioid-use disorder:
    • Decreases cravings
    • Decreases risk of overdose
  • Alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome
Methylnaltrexone Mu: competitive antagonist in the GI tract (does not cross the blood– brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification barrier) Opioid-induced constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea

Comparison of Opioid Analgesic Medications

The following table compares and contrasts characteristics of the opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation analgesics:

Table: Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors subtypes
Medication and formulation Receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors effects Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics Important facts
Opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation agonists
Morphine Strong agonist
  • M: hepatic glucuronidation
  • H: approximately 2–4 hr
Metabolite has potential neuroexcitation effects.
Fentanyl Strong agonist Transdermal formulation for extended-release delivery
Hydromorphone Strong agonist
  • M: hepatic glucuronidation
  • H: approximately 2–3 hr
  • Preferred opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation in renal impairment
  • Metabolite has potential neurotoxicity
Codeine Moderate agonist Schedule III in combination with acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen
Oxycodone Moderate agonist Frequently combined with acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen
Hydrocodone Hydrocodone Narcotic analgesic related to codeine, but more potent and more addicting by weight. It is used also as cough suppressant. Neonatal Abstinence Syndrome Moderate agonist
  • M: CYP2D6
  • H: approximately 4 hr
Frequently combined with acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen
Tramadol
  • Selective mu receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors agonist
  • Serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS reuptake inhibitor
  • Norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake inhibitor
  • A racemic mixture of 2 enantiomers
  • Toxic doses cause CNS excitation and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
Methadone
  • Strong agonist at opioid Opioid Compounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis. Constipation receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Antagonist at NMDA receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • M: CYP3A4 CYP3A4 Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers), CYP2D6
  • H: Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables, 8–59 hr
  • NMDA antagonistic effects make it useful in severe neuropathic pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Potential for torsades de pointes Torsades de pointes A malignant form of polymorphic ventricular tachycardia that is characterized by heart rate between 200 and 250 beats per minute, and QRS complexes with changing amplitude and twisting of the points. The term also describes the syndrome of tachycardia with prolonged ventricular repolarization, long qt intervals exceeding 500 milliseconds or bradycardia. Torsades de pointes may be self-limited or may progress to ventricular fibrillation. Ventricular Tachycardia
  • Incomplete cross-tolerance with other opioids
Agonist–antagonists
Nalbuphine
  • Mu: partial antagonist
  • Kappa: agonist
  • M: hepatic glucuronidation
  • H: 5 hr
  • Not associated with euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy or respiratory depression
  • Lower risk of addiction Addiction Substance use disorders are a significant cause of morbidity and mortality, especially among adolescents and young adults. A substance-related and addictive disorder is the continued use of a substance despite harmful consequences; these include significant impairment to one’s health or relationships or failure to fulfill major responsibilities at work, school, or home because of substance use. Substance-Related and Addictive Disorders
Buprenorphine
  • Mu: weak partial agonist
  • Kappa: weak antagonist
  • Delta: weak antagonist
  • Blocks binding of/displaces other full agonist opioids
  • Produces euphoria Euphoria An exaggerated feeling of physical and emotional well-being not consonant with apparent stimuli or events; usually of psychologic origin, but also seen in organic brain disease and toxic states. Hepatic Encephalopathy, but with ceiling effect
  • May precipitate withdrawal in opioid-tolerant patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
H: elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy half-life Half-Life The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. Pharmacokinetics and Pharmacodynamics
M: metabolism
NMDA: N-methyl-D-aspartate (NMDA) receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
SL: sublingual

References

  1. Schumacher, M.A., Basbaum A.I., Naidu R.K. (2021). Opioid agonists & antagonists. In Katzung, B.G., Vanderah, T.W. (Eds.), Basic & Clinical Pharmacology, 15th ed. McGraw-Hill. https://accessmedicine-mhmedical-com.ezproxy.unbosque.edu.co/content.aspx?bookid=2988&sectionid=250599194 
  2. Jamison, R.N., Mao, J. (2015). Opioid analgesics. Mayo Clin Proc 90:957–968. https://pubmed.ncbi.nlm.nih.gov/26141334/
  3. Guy, G.P., et al. (2017). Vital signs: changes in opioid prescribing in the United States, 2006-2015. MMWR Morb Mortal Wkly Rep 66:697–704. https://www.cdc.gov/mmwr/volumes/66/wr/mm6626a4.htm
  4. Aubrun, F., et al. (2019). Revision of expert panel’s guidelines on postoperative pain management. Anaesth Crit Care Pain Med 38:405–411. https://pubmed.ncbi.nlm.nih.gov/30822542/
  5. Zöllner, C., Stein, C. (2007). Opioids. Handb Exp Pharmacol. (177), 31–63. https://pubmed.ncbi.nlm.nih.gov/17087119/
  6. Aiyer, R., Mehta, N., Gungor, S., Gulati, A. (2018). A systematic review of NMDA receptor antagonists for treatment of neuropathic pain in clinical practice. Clin J Pain 34:450–467. https://pubmed.ncbi.nlm.nih.gov/28877137/
  7. Crockett, S.D., et al., American Gastroenterological Association Institute Clinical Guidelines Committee. (2019). American Gastroenterological Association Institute guideline on the medical management of opioid-induced constipation. Gastroenterology 156:218–226. https://pubmed.ncbi.nlm.nih.gov/30340754/
  8. Dowell, D., Haegerich, T.M., Chou, R. (2016). CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA 315:1624–1645. https://pubmed.ncbi.nlm.nih.gov/26977696/
  9. Pandharipande, P., McGrane, S. (2020). Pain control in the critically ill adult patient. UpToDate. Retrieved July 25, 2021, from https://www.uptodate.com/contents/pain-control-in-the-critically-ill-adult-patient
  10. Strain, E. (2021). Opioid use disorder: epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis. UpToDate. Retrieved July 25, 2021, from https://www.uptodate.com/contents/opioid-use-disorder-epidemiology-pharmacology-clinical-manifestations-course-screening-assessment-and-diagnosis
  11. Pasternak, G.W. (2014). Opiate pharmacology and relief of pain. Journal of Clinical Oncology 32:1655–1661. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031189/
  12. Pathan, H., Williams, J. (2012). Basic opioid pharmacology: an update. British Journal of Pain 6(1):11–16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4590096/
  13. Ghelardini, C., Mannelli, L.D.C., Bianchi, E. (2015). The pharmacological basis of opioids. Clinical Cases in Mineral and bone metabolism. 12:219–221. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708964/
  14. Centers for Disease Control and Prevention. (n.d.). Calculating total daily dose of opioids for safer dosage. Retrieved July 25, 2021, from https://www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf

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