PHAR: Opioid Analgesics

Question 1

Most systemic analgesics are based off of what two drug categories?

Answer 1

• Opioids.
  
  • Active inhibitory systems.
• Salicylates.
  
  • Inhibit prostaglandin synthesis.
    
    • COX inhibitors, NSAIDs.

Question 2

Describe endorphins and their mechanism of action.

Answer 2

Endogenous opioid peptide.

• Endogenous = produced within the body.
• Peptide that binds to opioid receptors in the brain.

Note: similarity in structure between opioid drug morphine and endogenous opioid peptide enkephalin.

Question 3

• What are the structure of the opioid receptors
• What are the three classes of receptors?

Answer 3

• Around 400 amino acids.
  
  • Around 7 transmembrane domains.
• Classes: µ (mu), κ (kappa), δ (delta) → 90% of amino acids identical.
  
  • Mu → M → morphine.

Question 4

• Which two components of the CNS contain opioid receptors?
  
  • Which receptors?
• Which opioid receptor is found in the PNS?

Answer 4

• Brain.
  
  • Brain stem (relevant for analgesia) (μ).
  • κ more prelevant in other components such as the limbic system (associated with abuse and addiction).
• Dorsal horn of the spinal cord.
  
  • Presynaptic (relevant for analgesia) (μ > δ).
• ​Periphery.
  
  • On nociceptive fibres.
  • Drugs won’t cross blood-brain barrier

Question 5

• Activation of the μ receptor leads to what side effects?

Answer 5

• Supraspinal analgesia.
• Miosis.
  
  • Excessive pupil constriction.
• Euphoria.
• Respiratory depression.
  
  • Can cause death.
• Physical dependence.

Question 6

• Name three μ agonists.
• Name one mixed agonist-antagonist.
• Name two opioid receptor antagonist.
• Name some of their benefits.

Answer 6

​AGONIST

• Morphine.
• Methadone.
• Buprenorphine.
  
  • Less respiratory depression.

MIXED AGONIST/ANTAGONIST

• Nalbuphine.
  
  • μ antagonist, κ agonist.

ANTAGONISTS

• Naloxone.
  
  • Fast-acting, potent antagonist to stop respiratory depression.
• Naltrexone.
  
  • Long-acting, used for treatment of drug addiction.

Question 7

List eight adverse side effects of opioids.

Answer 7

• Respiratory depression.
  
  • Worst side effect, potentially fatal.
• Nausea/vomiting.
• Constipation.
• Sedation.
• Hallucinations.
• Confusion.
• Physical dependence and tolerance.
• Psychological dependence/abuse.

Question 8

• Define tolerance and physical dependence in the context of opioids.
• Differentiate them from addiction.

Answer 8

• Tolerance = PHYSIOLOGICAL TERM.
  
  • Physiological adaptation to the chronic effects of opioids.
  • Body adapts so dose needs to be increased.
  • Tolerance can disappear very quickly.
  • Doesn’t imply addiction.
• Physical dependence = withdrawal symptoms when you stop taking the drug.
  • Nausea, vomiting, anorexia, diarrhoea, sweating, shivering, anxiety, depression.
  • Nearly universal with opioid use longer than one week.
  • Can be avoided by tapering opioid gradually.
• Addiction = Compulsive use of a substance despite harm.
  
  • Tolerance and physical dependence with opioids are not indicative of addiction.
  • Effects compounded by tolerance and physical dependence.

Question 9

Define opiophobia.

Answer 9

Customary underutilisation of opioids for unfounded fears of creating dependence and addiction.

Question 10

What are the issues associated with chronic pain states and the use of opioid treatment?

Answer 10

• Other factors need to be addressed that opioids may not necessarily address → opioids can be the ‘easy way out’ without addressing these other factors.
  
  • Suffering.
  • Dysfunction.
  • Mood states.
  • Psychosocial factors.
  • Dependence on health system.
• Opioids activate glia cells → more pain (opioid-induced hyperalgesia).
• Can lead to abuse.
• Useful in only a small subpopulation of patients.

Question 11

• What components are required for opioids to be prescribed?
• Give an example of pain where opioids WOULDN’T be prescribed.

Answer 11

• A full assessment process looking at/including:
  
  • A pain diagnosis.
  • Mental health.
  • Alcohol/drug dependency.
  • A trial of non-opioid analgesia + non-drug treatment.
  • Corroborating history from other health professionals.
• Never prescribe opioids for headaches.
  • Makes it worse.
  • Also fibromyalgia and non-specific lower back pain.

Question 12

What are the four elements to review the pain diagnosis and comorbid conditions?

Answer 12

• Analgesia.
• Activity.
• Adverse effects.
• Aberrant behaviour.

Question 13

• Codeine isn’t an opiate, but metabolises in the liver to produce _____.
  
  • Which enzyme is used in this process?
  • What can happen in the case of fast metabolisers?
• Codeine is a weak opioid, and its efficacy hasn’t always been proven. Why is it still used? (2 points)

Answer 13

• Codeine isn’t an opiate, but metabolises in the liver to produce morphine. (codeine = prodrug)
  
  • CYP2D6.
  • Amount of morphine you produce is entirely dependent on the demethylation effects of CYP2D6, an enzyme that is lacking in some patients.
  • Fast metabolisers → can die from ‘normal’ doses of codeine.
• Acceptable to patients, and convenient for prescribers.

Question 14

• What category of opioid does tramadol fall under, strong, atypical, or weak opioid?
  
  • Why does this make it suitable for clinical practice.
• What is it’s mechanism/s of action?

Answer 14

• Tramadol = atypical opioid.
  
  • As pure opioid effects are lower, less risk of addiction.
• Three mechanisms of action.
  
  • Opioid effect: μ-opioid receptor agonist.
  • SRI: serotonin reuptake inhibitor.
  • NRI: noradrenaline reuptake inhibitor.

Question 15

• When is tramadol recommended/advisable?
• What are some common side effects?

Answer 15

• Useful in situations where one wants to avoid or reduce opioid adverse effects like:
  
  • Respiratory depression.
  • Constipation.
  • Abuse.
  • Sedation/confusion
• Neuropathic pain.

SIDE EFFECTS

• Nausea.
• Vomiting.
• Confusion.
• Interaction with other serotonergic drugs (antidepressants).
  
  • Don’t mix serotonergic drugs with tramadol.

Question 16

• What are the mechanism/s of action of tapentadol?
• How does it differ from tramadol?
• How does it compare with morphine (and opioids in general) in terms of analgesia?

Answer 16

• Atypical opioid.
• Dual mechanism:
  
  • MOR (mu opioid receptor agonist).
  • NRI (noradrenaline reuptake inhibitor).
• No SRI effects, so nasty serotonin effects removed.
• Equianalgesic.
  
  • But 1/18th of morphine activity on opioid receptor.