Pharmacology of Opioid Analgesics

Opioid Analgesics: Introduction

Opioid analgesics are a class of drugs primarily used for pain management. They work by binding to specific receptors in the brain and spinal cord, reducing the perception of pain. Derived from the opium poppy or synthesized in the lab, opioids have been used for centuries for their analgesic and sedative properties.

Classification Based on Nature:

  1. Natural Opiates: These are directly derived from the opium poppy.

    • Morphine
    • Codeine
    • Thebaine
  2. Semi-synthetic Opioids: These are chemically modified derivatives of natural opiates.

    • Heroin (derived from morphine)
    • Oxycodone (derived from thebaine)
    • Hydrocodone (derived from codeine)
    • Hydromorphone (derived from morphine)
  3. Synthetic Opioids: These are not derived from opium but are synthesized in the lab and have similar effects.

    • Fentanyl
    • Methadone
    • Tramadol
    • Meperidine (Pethidine)
  4. Opioid Antagonists: These compounds block the effects of opioids.

    • Naloxone
    • Naltrexone

Classification Based on Efficacy:

  1. Strong Agonists: These bind with high affinity to opioid receptors and produce significant analgesic effects.

    • Morphine
    • Fentanyl
    • Methadone
    • Hydromorphone
    • Oxymorphone
  2. Moderate Agonists: These produce moderate analgesic effects.

    • Codeine
    • Oxycodone
    • Hydrocodone
    • Dihydrocodeine
  3. Weak Agonists: These have a lower affinity for opioid receptors and produce milder analgesic effects.

    • Tramadol
    • Meperidine (Pethidine)
  4. Mixed Agonist-Antagonists: These can act as agonists on certain opioid receptors and antagonists on others.

    • Buprenorphine (partial agonist at mu receptors and antagonist at kappa receptors)
    • Nalbuphine (agonist at kappa receptors and antagonist at mu receptors)
    • Pentazocine (agonist at kappa receptors and weak antagonist at mu receptors)
  5. Antagonists: These block the effects of opioids.

    • Naloxone
    • Naltrexone

This classification provides a comprehensive overview of opioid analgesics based on their origin and efficacy. It’s essential to note that the efficacy of an opioid can vary among individuals, and the choice of an opioid should be based on the clinical scenario and individual patient needs.

Mechanism of Action of Opioid Analgesics:

  1. Binding to Opioid Receptors: Opioid analgesics, such as morphine, fentanyl, and others, bind to specific receptors in the central nervous system. These receptors include mu (μ), delta (δ), and kappa (κ).

  2. Inhibition of Pain-Transmitting Neurons: Once opioids bind to these receptors, they inhibit the activity of pain-transmitting neurons. This means that these neurons are less likely to send pain signals to the brain.

  3. Reduction in Neurotransmitter Release: The binding of opioids to their receptors leads to a reduction in the release of certain neurotransmitters that are involved in pain transmission.

  4. Decreased Pain Perception: As a result of the reduced neurotransmitter release, there is a decreased perception of pain in the brain. This is how opioids provide their analgesic or pain-relieving effect.

 

Mechanism of action of Opioid Analgesics

This mechanism underscores the potency of opioids in managing pain but also highlights the importance of careful administration due to potential side effects like respiratory depression.

Pharmacokinetics of Opioid Analgesics:

1. Absorption

  • How the drug enters the bloodstream after administration.

    • Morphine: Administered orally, intravenously, or through other routes. Oral absorption can be erratic due to significant first-pass metabolism in the liver.
    • Oxycodone: Available in immediate-release and controlled-release oral formulations. It’s well absorbed from the gastrointestinal tract.
    • Fentanyl: Often administered as a transdermal patch, allowing for continuous absorption through the skin over time. It can also be given intravenously.

2. Distribution

  • How the drug spreads throughout the body.

    • Morphine: Distributes widely in the body. It can cross the blood-brain barrier, leading to its central effects.
    • Hydrocodone: Like morphine, it has a wide distribution and can cross the blood-brain barrier.
    • Tramadol: Distributes throughout the body and has a high volume of distribution due to its lipophilic nature.

3. Metabolism

  • How the drug is broken down in the body, usually in the liver.

    • Morphine: Primarily metabolized in the liver to produce morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active and potent).
    • Codeine: Metabolized in the liver by the enzyme CYP2D6 to its active form, morphine.
    • Fentanyl: Undergoes hepatic metabolism, primarily by the CYP3A4 enzyme, producing inactive metabolites.

4. Excretion

  • How the drug and its metabolites are eliminated from the body.

    • Morphine: Excreted mainly through urine, both as unchanged drug and metabolites.
    • Oxycodone: Excreted in urine, primarily as metabolites.
    • Methadone: Excreted in urine, faeces, and sweat. It has a long half-life, leading to prolonged excretion.

In summary, the ADME profile of opioid analgesics varies depending on the specific drug, its formulation, and the route of administration. This pharmacokinetic information is crucial for healthcare professionals to determine the appropriate dosing regimen, monitor for potential drug interactions, and predict possible side effects.

Pharmacological Actions of Opioid Analgesics:

1. Central Nervous System (CNS)

  • Analgesia: The primary therapeutic effect of opioids is pain relief. They act on the brain and spinal cord to decrease the perception of pain.
  • Sedation: Opioids can induce drowsiness and a feeling of relaxation.
  • Euphoria: Some opioids can produce a sense of well-being or euphoria, which contributes to their potential for misuse and addiction.
  • Respiratory Depression: A significant side effect of opioids is the suppression of the respiratory center in the brain, leading to decreased breathing rate and depth. This can be life-threatening in overdose situations.
  • Cough Suppression: Opioids, especially codeine, suppress the cough reflex by acting on the cough center in the brain.
  • Miosis: Opioids cause pinpoint pupils, a condition called miosis.

2. Gastrointestinal System

  • Constipation: Opioids reduce gastrointestinal motility, leading to constipation, a common side effect.
  • Nausea and Vomiting: Opioids can stimulate the chemoreceptor trigger zone (CTZ) in the brain, leading to nausea and vomiting.

3. Cardiovascular System

  • Vasodilation: Some opioids, like morphine, can cause peripheral vasodilation, leading to flushing and warmth.
  • Orthostatic Hypotension: Opioids can lead to a drop in blood pressure upon standing, known as orthostatic hypotension.

4. Endocrine System

  • Hormonal Changes: Chronic opioid use can lead to decreased levels of sex hormones, affecting libido and causing menstrual irregularities in women and reduced testosterone levels in men.

5. Urinary System

  • Urinary Retention: Opioids can increase the tone of the bladder sphincter and decrease bladder contractions, leading to difficulty in urination.

6. Immune System

  • Immunosuppression: Some studies suggest that chronic opioid use might suppress the immune system, though the clinical significance of this is still under investigation.

7. Musculoskeletal System

  • Muscle Rigidity: High doses of potent opioids like fentanyl can cause muscle rigidity, especially in the chest wall.

Therapeutic Usesof Opioid Analgesics:

1. Pain Management

Opioids are primarily used to manage moderate to severe pain, whether acute (e.g., post-surgical pain) or chronic (e.g., cancer-related pain).

  • Morphine: Often used for severe pain, especially in palliative care settings.
  • Oxycodone: Used for moderate to severe pain. Available in both immediate-release and extended-release formulations.
  • Hydrocodone: Commonly prescribed for moderate pain and often combined with acetaminophen.
  • Fentanyl: Used for chronic pain management, especially in cancer patients. Available as patches, lozenges, and injectable forms.
  • Tramadol: Prescribed for moderate to moderately severe pain.

2. Cough Suppression

Some opioids have antitussive properties, making them useful in suppressing persistent coughs.

  • Codeine: Often combined with other medications in prescription cough syrups.
  • Dextromethorphan: A non-opioid derivative with antitussive effects.

3. Diarrhea Control

Certain opioids can be used to manage diarrhoea due to their effect on slowing intestinal motility.

  • Loperamide (Imodium): An over-the-counter opioid agonist used specifically for diarrhoea control. It doesn’t cross the blood-brain barrier in significant amounts, so it lacks the analgesic and euphoric properties of other opioids.
  • Diphenoxylate (combined with atropine as Lomotil): Used for the treatment of diarrhoea.

4. Opioid Dependence Treatment

Some opioids are used in the management and treatment of opioid dependence and withdrawal.

  • Methadone: Used in opioid replacement therapy. It helps in reducing cravings and withdrawal symptoms in individuals addicted to heroin or other opioids.
  • Buprenorphine: Often combined with naloxone (as Suboxone) and used in medication-assisted treatment (MAT) for opioid addiction.

5. Anesthesia

Certain opioids are used as adjuncts in anesthesia to enhance pain control during and after surgeries.

  • Fentanyl: Commonly used in surgical settings due to its rapid onset and short duration of action.
  • Remifentanil: A very short-acting opioid used during surgeries.

Side Effects of Opioid Analgesics:

1. Respiratory Depression

  • Reduced rate and depth of breathing, which can be life-threatening in overdose situations.
  • Morphine is a classic opioid that can cause significant respiratory depression, especially when given in high doses or to opioid-naive patients.

2. Constipation

  • Opioids slow down the movement of the intestines, leading to constipation.
  • Codeine, often used for mild to moderate pain and as a cough suppressant, frequently causes constipation.

3. Nausea and Vomiting

  • Opioids can stimulate the chemoreceptor trigger zone (CTZ) in the brain, leading to nausea and vomiting.
  • Hydrocodone, especially when initiated, can cause nausea in some patients.

4. Sedation and Drowsiness

  • Opioids can induce drowsiness and a feeling of relaxation.
  • Oxycodone, especially in its extended-release form, can cause significant sedation.

5. Pruritus (Itching)

  • Some patients experience itching, especially when opioids are administered via spinal or epidural routes.
  • Morphine, when given intrathecally or epidurally, can lead to pruritus.

6. Urinary Retention

  • Difficulty in urination due to increased tone of the bladder sphincter and decreased bladder contractions.
  • Tramadol, apart from its analgesic effects, can cause urinary retention in some patients.

7. Miosis (Pinpoint Pupils)

  • Opioids cause constriction of the pupils.
  • Heroin, an illicit opioid, often causes miosis, which can be a clinical sign of its use or overdose.

8. Dependence and Addiction

  • Chronic use can lead to physical dependence (withdrawal symptoms upon cessation) and addiction (compulsive drug-seeking behavior).
  • Fentanyl, due to its high potency, has a high potential for dependence and misuse.

9. Hyperalgesia

  • An increased sensitivity to pain, paradoxically caused by prolonged opioid use.
  • Methadone, used for chronic pain and opioid replacement therapy, can lead to hyperalgesia with long-term use.

10. Hormonal Changes

  • Chronic opioid use can lead to reduced levels of sex hormones.
  • Buprenorphine, used in opioid addiction treatment, can cause hormonal imbalances with prolonged use.

11. Immunosuppression

  • Some studies suggest that opioids might suppress the immune system.
  • Morphine, especially with chronic use, has been associated with potential immunosuppressive effects.

Contraindications of Opioid Analgesics:

1. Respiratory Depression

  • Patients with compromised respiratory function or conditions like severe asthma, chronic obstructive pulmonary disease (COPD), or acute respiratory distress syndrome (ARDS) are at higher risk of respiratory depression with opioids.

2. Paralytic Ileus

  • Opioids can exacerbate paralytic ileus, a condition where the intestines stop moving without any blockage.

3. Head Injury

  • Opioids can increase intracranial pressure, which can be detrimental in patients with head injuries.

4. Hypersensitivity

  • Patients with a known allergy or hypersensitivity to a specific opioid or any of its components should avoid that opioid.

5. Severe Hepatic Impairment

  • Opioids metabolized in the liver can accumulate in patients with severe hepatic impairment, increasing the risk of side effects.

6. Severe Renal Impairment

  • Some opioids and their metabolites are excreted by the kidneys. In patients with severe renal impairment, these drugs can accumulate.

7. Concurrent Use with MAO Inhibitors

  • Combining opioids with monoamine oxidase inhibitors (MAOIs) can lead to serotonin syndrome or exaggerated opioid effects.

8. Biliary Tract Disease

  • Opioids can cause spasm of the sphincter of Oddi, exacerbating conditions like acute pancreatitis or biliary colic.

9. Pregnancy

  • Chronic use of opioids during pregnancy can lead to neonatal opioid withdrawal syndrome.

Drug Interactions of Opioid Analgesics:

1. Benzodiazepines

  • Both opioids and benzodiazepines depress the central nervous system (CNS). When combined, there’s an increased risk of respiratory depression, sedation, and overdose.
  • Example: Combining morphine with diazepam can lead to profound sedation and respiratory depression.

2. Other CNS Depressants

  • Combining opioids with other CNS depressants can enhance the sedative effects, leading to increased respiratory depression and risk of overdose.
  • Example: Combining oxycodone with alcohol can intensify the sedative effects of both substances.

3. Monoamine Oxidase Inhibitors (MAOIs)

  • MAOIs can potentiate the effects of opioids, leading to increased respiratory depression and the risk of serotonin syndrome.
  • Example: Meperidine and MAOIs like phenelzine can lead to severe interactions, including serotonin syndrome.

4. Serotonergic Drugs

  • Combining opioids with drugs that increase serotonin levels can lead to serotonin syndrome, a potentially life-threatening condition.
  • Example: Combining tramadol with SSRIs like fluoxetine can increase the risk of serotonin syndrome.

5. Muscle Relaxants

  • Opioids can enhance the respiratory depressant effects of muscle relaxants.
  • Example: Hydrocodone combined with carisoprodol can lead to increased sedation and respiratory depression.

6. Anticholinergic Drugs

  • Both opioids and anticholinergics can cause constipation, urinary retention, and dry mouth. Their combined use can exacerbate these effects.
  • Example: Combining codeine with antihistamines like diphenhydramine can intensify anticholinergic side effects.

7. CYP450 Enzyme Interactions

  • Some opioids are metabolized by the CYP450 enzyme system in the liver. Drugs that inhibit or induce these enzymes can affect opioid levels.
  • Example: CYP3A4 inhibitors like ketoconazole can increase the levels of fentanyl, enhancing its effects and side effects.

8. Mixed Agonist/Antagonist Opioids

  • Drugs like buprenorphine, which act as partial agonists, can precipitate withdrawal symptoms if given to someone dependent on full opioid agonists.
  • Example: Administering buprenorphine to a patient dependent on morphine can lead to withdrawal symptoms.

9. Antihypertensive Drugs

  • Opioids can potentiate the effects of antihypertensive drugs, leading to enhanced blood pressure-lowering effects.
  • Example: Morphine combined with beta-blockers like metoprolol can lead to significant hypotension.

Conclusion:

Opioid analgesics are powerful pain-relieving agents with a range of therapeutic uses. However, their potential for side effects, contraindications, and drug interactions necessitates careful use and monitoring. The rise in opioid addiction and overdose in recent years underscores the importance of judicious prescribing and patient education.

Disclaimer: This article is for informational purposes only and should not be taken as medical advice. Always consult with a healthcare professional before making any decisions related to medication or treatment.


Key Points on Opioids:

  1. Opioids are substances obtained from the crude extract of the poppy plant (Papaver somniferum).
    Opioids
    Source: https://en.wikipedia.org/wiki/Papaver_somniferum
  2. Morphine is the prototype opioid and acts on μ, κ, and δ receptors. Endorphins, dynorphins, and enkephalins are endogenous peptides that produce analgesic effects on opioid receptors.
  3. Sufentanil is the most potent opioid, while meperidine and propoxyphene are the weakest. Morphine is primarily metabolized into M3G and M6G, which can lead to seizures or prolonged effects in certain cases. Pethidine can result in seizures due to the accumulation of norpethidine.
  4. Some opioids can increase heart rate (pethidine and pentazocine); others may lower blood pressure and cause constipation, worsening biliary colic, and bronchoconstriction in asthmatics.
  5. Buprenorphine, nalbuphine, pentazocine, dezocine, and butorphanol are examples of mixed agonists-antagonists.
  6. Opioids are used for pain relief, coughing suppression, pre-anaesthesia, and treatment of non-infectious diarrhoea. They can be administered orally, rectally, IV, IM, intrathecal, or epidural.
  7. Adverse effects of opioids include respiratory depression, nausea, vomiting, constipation, urinary retention, itching, and dysphoria. Tolerance occurs, except for miosis, constipation, and convulsions. Opioids are addictive and can cause withdrawal syndrome upon discontinuation.
  8. Opioids should be used cautiously in patients with a head injury, pulmonary, hepatic, or renal dysfunction, infants, and the elderly.
  9. Naloxone, naltrexone, and nalmefene are opioid receptor antagonists and alvimopan and methylnaltrexone are peripheral opioid antagonists.
  10. Naloxone is the most commonly used opioid antagonist and has a short half-life of approximately 30-60 minutes. It is used to treat opioid overdose, as it rapidly reverses the respiratory depression caused by opioids. 
  11. Naltrexone has a longer half-life of 4-6 hours and is used in treating opioid dependence. 
  12. Nalmefene is used for the management of opioid overdose, similar to naloxone, and has a slightly longer half-life compared to naloxone. 
  13. Alvimopan and methylnaltrexone are peripheral opioid antagonists, which means they block the peripheral effects of opioids, such as constipation, without affecting the central effects, such as pain relief. They are used to treat postoperative ileus and opioid-induced constipation.

Overall, opioids are powerful pain-relieving drugs with various clinical uses, but they also have several adverse effects and can be addictive. Careful consideration and monitoring are required when using opioids, and opioid antagonists play an essential role in reversing the effects of opioids in case of overdose or dependence.

Disclaimer: This article is for informational purposes only and should not be taken as medical advice. Always consult with a healthcare professional before making any decisions related to medication or treatment.


These medications play a crucial role in the management of various medical conditions, such as chronic pain, severe injury, or postoperative pain. Understanding the mechanisms of action, indications, and potential side effects of these drugs is essential for healthcare providers to provide effective care for their patients.


It is recommended to practice and test your understanding of opioids through self-assessment. I suggest attempting the quiz/test, which does not collect any user data, to reinforce your understanding and grasp important aspects of these drugs.

QUIZ: Please note that the quiz can only be accessed on desktops/laptops

[qsm quiz=3]

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always seek the advice of a healthcare provider with any questions regarding a medical condition.

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