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 Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Known for their remarkable efficacy, opioids induce their effects (analgesia, euphoria, and sedation) by interacting with opioid 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. General Structure of the Nervous System. Opiates/opioids have adverse effects that include respiratory depression, nausea and vomiting, decreased GI 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, 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.

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Pharmacodynamics

Definitions

Opioids are a class of natural or synthetic drugs that act on opioid receptors to provide analgesia and CNS effects.

  • Opiates: a subclass of opioids, consisting of alkaloid drugs derived naturally from the opium poppy
  • Endorphins: endogenous peptides that provide pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain relief by binding to opioid receptors
    • Beta-endorphins
    • Dynorphins
    • Enkephalins

Mechanism of action

  • There are 3 classical opioid receptors located in the central and peripheral nervous systems:
    • Mu
    • Kappa
    • Delta
  • Effect on opioid receptors:
    • Activation of opioid receptors → stimulation of coupled G-proteins 
    • ↓ Synaptic transmission → inhibit pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain signals:
      • Close presynaptic calcium channels → ↓ neurotransmitter release
      • Open postsynaptic potassium channels → outward movement of K → hyperpolarization → ↓ neuronal excitability
  • Opioids can be:
    • Agonists
    • Partial agonists: have ↑ receptor affinity, but ↓ receptor efficacy
    • Agonist-antagonists: may have agonist and antagonist effects at different opioid receptors

Opioid receptors

The following table summarizes and compares the effects of opioid receptors:

Table: Opioid receptor subtypes
Mu (μ) receptor Kappa (κ) receptor Delta (δ) receptor
Effect on analgesia Spinal and central Spinal Spinal
Effect on GI tract Slowed gastric transit
Other effects
  • Respiratory depression
  • Euphoria
  • Sedation
  • Miosis
  • 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
  • Dysphoria
  • Sedation
  • Diuresis
  • Anxiolysis
  • Hormone changes
Habituation None None Tolerance
Agonists
  • Beta-endorphins
  • Morphine
  • Fentanyl
  • Dynorphins
  • Mixed-action agonists
  • Enkephalins
  • Morphine
  • Codeine

Physiology effects

CNS: 

  • Analgesia
  • Euphoria
  • Dysphoria
  • Sedation
  • Respiratory depression 
  • Bradycardia
  • Cough suppression
  • Miosis
  • Truncal rigidity
  • Nausea and vomiting
  • Tolerance
  • Opioid-induced hyperalgesia 
  • Opioid-induced allodynia

Peripheral:

  • ↓ GI 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 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 of: 
    • Antidiuretic hormone (ADH)
    • Prolactin
    • 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 analgesics in relation to the strength of the drug

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

Pharmacokinetics

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
    • 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
    • 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
    • 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
    • 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
  • 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:
    • CYP3A4
    • CYP2D6
    • Hepatic glucuronidation
  • Excretion: renal

Classification

Action on receptors

The opioid analgesics can be classified on the basis of their activity on opioid receptors:

  • Opioid agonists:
    • Strong agonists:
      • Fentanyl
      • Hydromorphone
      • Levorphanol
      • Meperidine
      • Methadone
      • Morphine
      • Oxymorphone
    • Moderate agonists:
      • Codeine
      • Hydrocodone
      • Oxycodone
    • Weak agonists: propoxyphene
  • Agonist–antagonist: 
    • Nalbuphine
    • Buprenorphine

Origin

Opioids can be characterized as:

  • Natural (opiates):
    • Morphine
    • Codeine
  • Semisynthetic opioids:
    • Heroin
    • Oxycodone
    • Hydrocodone
    • Hydromorphone
    • Oxymorphone
  • Synthetic opioids:
    • Fentanyl
    • Methadone
    • Tramadol

Indications

Indications and uses

  • Pain:
    • Moderate to severe nociceptive pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain:
      • Surgical
      • Tumor-related pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
      • 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 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)
  • Anesthesia Anesthesia Anesthesiology is the field of medicine that focuses on interventions that bring a state of anesthesia upon an individual. General anesthesia is characterized by a reversible loss of consciousness along with analgesia, amnesia, and muscle relaxation. Anesthesiology: History and Basic Concepts before surgery 
  • Perioperative shivering

The following table summarizes the stepwise approach recommended for treating pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain:

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, and ganglion block

Equianalgesic dosing

  • Helpful when converting from one opioid to another
  • Helps avoid iatrogenic 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, so hydrocodone = 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 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.

Adverse Effects and Contraindications

Adverse effects

  • Nausea and vomiting
  • Constipation
  • Pruritus
  • Respiratory depression
  • CNS depression
  • Bradycardia
  • 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 (particularly with tramadol)
  • QT prolongation (particularly with methadone)
  • Opioid abuse and dependence
  • Opioid-induced hyperalgesia
  • Opioid-induced allodynia

Contraindications

Absolute:

  • Acute head injuries
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care
  • Impaired pulmonary function
  • Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). 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) 
  • Previous drug and/or alcohol rehabilitation 
  • Family or personal history of substance abuse

Relative:

  • Children < 1 year of age
  • History of depression or anxiety
  • 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 Increased Intracranial Pressure Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP)
  • 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 due to the BP-lowering effects
  • Opioid 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 (MAO) inhibitors (with meperidine) → hyperpyrexia syndrome
  • Variability exists with individual agents.

Tolerance and physical dependence

  • Tolerance:
    • A gradual loss in effectiveness with therapeutic doses
    • Need for progressive dose escalations to achieve previous levels of analgesia, euphoria, etc.
    • Reflects change in opioid receptor density and receptor physiology after prolonged and/or repeated agonist exposure 
  • Dependence:
    • Phenomenon of drug withdrawal symptoms triggered by cessation of dose deescalation:
      • Muscle aches
      • Restlessness
      • Anxiety
      • Lacrimation
      • Rhinorrhea
      • 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
      • Piloerection
      • Nausea and vomiting
      • Mydriasis
      • Tachycardia
      • 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

Opioid Antagonists

The following table compares the most common opioid antagonists:

Table: Comparison of the most common opioid antagonists
Medication Mechanism Indication Side effects
Naloxone Mu: competitive antagonist
  • Emergent reversal from opioid overdose
  • Reduces sedation and respiratory depression
Opioid withdrawal
Naltrexone Competitive antagonist at mu, kappa, and delta receptors
  • Opioid-use disorder:
    • Decreases cravings
    • Decreases risk of overdose
  • Alcoholism
  • Opioid withdrawal
  • Hepatotoxicity
Methylnaltrexone Mu: competitive antagonist in the GI tract (does not cross the blood–brain 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 Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Nausea
  • 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 analgesics:

Table: Opioid receptor subtypes
Medication and formulation Receptor effects Pharmacokinetics Important facts
Opioid agonists
Morphine Strong agonist
  • M: hepatic glucuronidation
  • H: approximately 2–4 hr
Metabolite has potential neuroexcitation effects.
Fentanyl Strong agonist
  • M: CYP3A4
  • IV H: approximately 2–4 hr
  • Transdermal H: 20–27 hr
Transdermal formulation for extended-release delivery
Hydromorphone Strong agonist
  • M: hepatic glucuronidation
  • H: approximately 2–3 hr
  • Preferred opioid in renal impairment
  • Metabolite has potential neurotoxicity
Codeine Moderate agonist
  • M: CYP2D6, CYP3A4
  • H: approximately 3 hr
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
  • M: CYP3A4, CYP2D6
  • H: approximately 4–6 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
Hydrocodone 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 agonist
  • Serotonin reuptake inhibitor
  • Norepinephrine reuptake inhibitor
  • M: CYP2D6, CYP3A4, glucuronidation
  • H: approximately 6 hr
  • 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 receptor
  • Antagonist at NMDA receptor
  • M: CYP3A4, CYP2D6
  • H: Variable, 8–59 hr
  • NMDA antagonistic effects make it useful in severe neuropathic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Potential for torsades de pointes
  • Incomplete cross-tolerance with other opioids
Agonist–antagonists
Nalbuphine
  • Mu: partial antagonist
  • Kappa: agonist
  • M: hepatic glucuronidation
  • H: 5 hr
  • Not associated with euphoria 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
  • M: CYP3A4
  • H: approximately 37 hr (sublingual)
  • Blocks binding of/displaces other full agonist opioids
  • Produces euphoria, but with ceiling effect
  • May precipitate withdrawal in opioid-tolerant patients
H: elimination half-life
M: metabolism
NMDA: N-methyl-D-aspartate (NMDA) receptor
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/
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  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/
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