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. 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. Opiates/opioids have adverse effects that include respiratory depression, nausea and vomiting, decreased GI motility and constipation, tolerance, dependence, and addiction.

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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 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 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) receptorKappa (κ) receptorDelta (δ) receptor
Effect on analgesiaSpinal and centralSpinalSpinal
Effect on GI tractSlowed gastric transit
Other effects
  • Respiratory depression
  • Euphoria
  • Sedation
  • Miosis
  • Modulation of hormones
  • Dysphoria
  • Sedation
  • Diuresis
  • Anxiolysis
  • Hormone changes
HabituationNoneNoneTolerance
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
  • Contraction of biliary smooth muscle → biliary colic
  • ↓ Renal plasma flow → ↓ renal function
  • Prolongation of labor
  • ↑ Secretion of: 
    • Antidiuretic hormone (ADH)
    • Prolactin
    • Somatotropin 
  • Flushing
  • Sweating
  • Urticaria
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
    • Liver
    • Kidneys
    • Spleen
  • Accumulation can occur in:
    • Skeletal muscle
    • Fatty tissue

Metabolism and excretion

  • Significant and variable 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:
      • Surgical
      • Tumor-related pain
      • Sickle cell crisis
    • Acute MI
    • Generally, opioid therapy is indicated only after more conservative analgesic measures have failed.
  • Dyspnea (particularly in end-of-life care)
  • Cough (codeine)
  • Diarrhea (loperamide)
  • Anesthesia before surgery 
  • Perioperative shivering

The following table summarizes the stepwise approach recommended for treating pain:

Table: WHO ladder governing analgesics
StepRecommended therapy
1Nonopioid analgesics
2Nonopioid analgesics + mild opioids (tramadol)
3Nonopioid analgesics + strong opioids (morphine, hydromorphone, and oxycodone)
4Invasive 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)*
DrugMME
Codeine0.15
Fentanyl transdermal (in mcg/hr)2.4
Hydrocodone1
Hydromorphone4
Methadone:
  • 1–20 mg/day
  • 21–40 mg/day
  • 41–60 mg/day
  • ≥ 61–80 mg/day
  • 4
  • 8
  • 10
  • 12
Morphine1
Oxycodone1.5
Oxymorphone3
*These dose conversions are estimated and cannot account for all individual differences in genetics and pharmacokinetics.

Adverse Effects and Contraindications

Adverse effects

  • Nausea and vomiting
  • Constipation
  • Pruritus
  • Respiratory depression
  • CNS depression
  • Bradycardia
  • 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
  • Impaired pulmonary function
  • Adrenal insufficiency (Addison’s disease) 
  • 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)
  • Increased intracranial pressure
  • 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
  • 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
      • Frequent yawning
      • Diarrhea
      • Abdominal cramping
      • Piloerection
      • Nausea and vomiting
      • Mydriasis
      • Tachycardia
      • 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
MedicationMechanismIndicationSide effects
NaloxoneMu: competitive antagonist
  • Emergent reversal from opioid overdose
  • Reduces sedation and respiratory depression
Opioid withdrawal
NaltrexoneCompetitive antagonist at mu, kappa, and delta receptors
  • Opioid-use disorder:
    • Decreases cravings
    • Decreases risk of overdose
  • Alcoholism
  • Opioid withdrawal
  • Hepatotoxicity
MethylnaltrexoneMu: competitive antagonist in the GI tract (does not cross the blood–brain barrier)Opioid-induced constipation
  • Abdominal pain
  • Nausea
  • Diarrhea

Comparison of Opioid Analgesic Medications

The following table compares and contrasts characteristics of the opioid analgesics:

Table: Opioid receptor subtypes
Medication and formulationReceptor effectsPharmacokineticsImportant facts
Opioid agonists
MorphineStrong agonist
  • M: hepatic glucuronidation
  • H: approximately 2–4 hr
Metabolite has potential neuroexcitation effects.
FentanylStrong agonist
  • M: CYP3A4
  • IV H: approximately 2–4 hr
  • Transdermal H: 20–27 hr
Transdermal formulation for extended-release delivery
HydromorphoneStrong agonist
  • M: hepatic glucuronidation
  • H: approximately 2–3 hr
  • Preferred opioid in renal impairment
  • Metabolite has potential neurotoxicity
CodeineModerate agonist
  • M: CYP2D6, CYP3A4
  • H: approximately 3 hr
Schedule III in combination with acetaminophen
OxycodoneModerate agonist
  • M: CYP3A4, CYP2D6
  • H: approximately 4–6 hr
Frequently combined with acetaminophen
HydrocodoneModerate agonist
  • M: CYP2D6
  • H: approximately 4 hr
Frequently combined with 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
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
  • 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
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/
  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/
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  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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