26. Opioid analgesic drugs. Morphine and codeine

Page created on June 12, 2019. Last updated on June 18, 2019 at 19:59

Introduction to nociception

The main type of peripheral sensory neuron that mediates pain is the polymodal nociceptor (PMN). This is non-myelinated C-type fibre that responds to thermal, mechanical and chemical stimuli. The chemical stimuli that act on PMNs include bradykinin, protons and vanilloids like capsaicin, which is what makes spicy food spicy. The sensitivity of PMNs is increased by prostaglandins, which explains the hyperalgesia that occurs during inflammation.

The descending inhibitory pathway is a pathway from the brain that inhibits PMNs, thereby decreasing pain. This pathway goes through the periaqueductal grey area and the rostral ventromedial medulla in the medulla oblongata and ends in the substantia gelatinosa in the spinal cord.

Introduction to opioid analgesics

Opioid receptors:

Opioids bind to and activate opioid receptors. The endogenous ligands for these receptors are the so-called endorphins. Three opioid receptors are important. These are the μ, κ and δ opioid receptors. Of these three the μ receptor is the most important for us as it causes the most analgesia, and it’s also responsible for some major unwanted effects, like respiratory depression, euphoria and dependence. Most clinically useful opioids are µ agonists with variable effect on the other opioid receptors.

All three opioid receptors are Gi-coupled receptors which open K+ channels in neurons. This causes hyperpolarization of the cells and inhibits release of other neurotransmitters.

These receptors should be pronounced “mew”, kappa and delta, respectively.


Opioids (more specifically µ receptor agonists) cause analgesia by multiple mechanisms:

  • The inhibit peripheral PMNs directly
  • They inhibit the ascending pain pathways in the substantia gelatinosa
  • They activate the descending inhibitory pathways
  • They trigger release of endogenous opioids

Opioids are more effective on continuous dull pain than sharp pain. They’re even less effective on neuropathic pain. They also decrease the emotional impact of the pain.

Adverse effects:

Opioids cause several adverse effects:

  • Sedation
    • Especially in elderly
  • Euphoria
    • Due to activation of the mesolimbic “reward” pathway
  • Respiratory depression
    • Due to decreased sensitivity of the respiratory centre to CO2
    • Chronic pain may counteract the respiratory depression
  • Constipation
    • Due to decreased peristalsis and increased tone of sphincters
  • Cough suppression
    • Due to decreased sensitivity of the “cough centre”
  • Nausea
    • Due to stimulation of the area postrema/chemosensitive trigger zone
  • Urinary retention
    • Due to contraction of the sphincters
  • Negative heart effects
    • Due to increased vagal tone
  • Miosis
  • Decreased release of GnRH and CRH
  • Decreased effectiveness of immune system
  • Itching
    • Due to histamine release
  • Acute pancreatitis
    • Due to contraction of the sphincter of Oddi

No tolerance develops to constipation, so it’s the most significant side effect of chronic opioid use. Chronic opioid use should be combined with high-fibre diet and laxatives.


Tolerance develops to some of the effects of opioids, but not to all. Pronounced tolerance develops to the analgesia, euphoria, respiratory depression and sedation, but minimal tolerance develops to the constipation and miosis.

Pharmacodynamic tolerance develops, where the expression of adenylyl cyclase is increased to counteract the Gi protein-mediated inhibition of the same enzyme.

Cross-tolerance refers to how building up a tolerance to one drug automatically builds up tolerance to another drug as well. Luckily there is very little cross-tolerance between different opioids, meaning that when tolerance has been developed to one opioid, switching to another opioid can return the analgesic effect.

Opioid-induced hyperalgesia:

Some patients who take opioids can develop increased sensitivity to certain pain stimuli, not necessarily the type of pain they take opioids for. This is paradoxical, and the exact mechanism is unknown. It’s mostly seen in people who take opioids for a long time.


Pregnancy: Chronic opioid use in pregnant women causes the foetus to become dependant and experience withdrawal.

Biliary colic, renal colic: Due to the sphincter-contracting effect of opioids.

Lung diseases, breathing problems: Due to respiratory depression.

Increased ICP: Due to pCO2 elevation due to respiratory depression.

Drug interactions:

Opioids should not be combined with sedatohypnotic drugs like benzos or alcohol, due to the risk of respiratory depression.

α2 agonists like clonidine increase the effects of opioids.

Combining opioids with MAO inhibitors or drugs that inhibit reuptake of monoamines like antidepressants or cocaine can cause serotonin syndrome.

Dependence, intoxication and withdrawal of opioids was described in topic 24.


Both morphine and codeine are natural opioids, which are extracted from the opium poppy plant. Morphine is often the first-line opioid to use as an analgesic because tolerance are withdrawal effects are not as common as with other opioids.


Acute (trauma, burns, surgery) and chronic pain (especially cancer-related pain).

Mechanism of action:

Strong µ opioid receptor agonist.


Oral, IV, intramuscular, epidural, spinal. Sustained-release oral preparations are often used for chronic pain.


Morphine is biotransformed into an active metabolite in the liver. This active metabolite is excreted by the kidneys.


In kidney failure the active metabolite of morphine accumulates. Dosage should be reduced in this case.


See section above.

Side effects:

See section above.



Mild pain. As a cough suppressant in case of severe dry cough.

Mechanism of action:

Codeine itself is a weak-moderate µ opioid receptor agonist. It’s metabolized into morphine.




Codeine is a prodrug that is metabolised into morphine in the liver by CYP2D6. Genetic differences can significantly influence how much of the codeine is metabolised into morphine. In most people only 10% of administered codeine is metabolised into morphine. In some people codeine has similar effects on the body as morphine due to high CYP2D6 activity.


In kidney failure the active metabolite of morphine accumulates. Dosage should be reduced in this case.

Side effects:

Constipation. Other side effects of opioids are not common.

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27. Opioid analgesic drugs. Semisynthetic, synthetic opioids, opioid antagonists

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Pharmacology 2

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