Week 5 - E - Pharmacology - Analgesia - Opioid receptors - Analgesic drugs - Who ladder, Opioids, NSAIDs, Neuropathic pain Tx

Question 1

What is the difference between an opiate and an opioid?

Answer 1

Opiates - these are agents extracted from opium or of a simila structure to those in opium - these are exogenous to central nervous system Opioids - these are any agents that act upon the opioid receptors (these include the exogenous opiates an man made substances but also any endoegenous peptides that act on opioid receptors)

Question 2

Strategies in the Pharmacological Management of Pain What is the pain ladder?

Answer 2

This is the WHO analgesic pain ladder - initially made for cancer patients but now used for all pain managements Originally published in 1986 for the management of cancer pain, it is now widely used by medical professionals for the management of all types of pain.

Question 3

Give examples of the non-opioid drugs given in rung 1,2or3 of the who ladder? Give examples of weak and strong opiods for rung 2 and 3 respectively?

Answer 3

• Rung 1 -
  
  • * Non-opioid - NSAIDs (aspirin, ibuprofen, diclofenac, naproxen, indometacin)
  • * Other non opioid drugs - paracetamol
• Rung 2
  
  • * Weak opioid - codeine and tramadol
• Rung 3
  
  • * Morphine, oxycodone and hydromorphone

Combinations of 1+2, or 1+3, are often used in moderate/ severe pain

Question 4

Physiology of pain modulation * Segmental anti-nociception – gate control theory * Supraspinal anti-nociception – descending pathways from brainstem What are the regions of the brain involved in pain and emotion?

Answer 4

This would be the cortex, amygadala, thalamus and hypothalamus The project back to the brainstem and spinal cord to modifiy important afferent input

Question 5

There are three very important regions in the brainstem that exhibit analgesic affect when stimulated. As it happens, one of these regions is in the midbrain, one in the pons and on ein the medulla What is the region in the midbrain known as? It surround the cerebral aqueduct that runs through the midbrain WHat is the function of the cerebral aqueduct?

Answer 5

The region in the midbrain important for alagesia when stimulated is the periaqueductal gray matter The function of the cerebral aqueduct is to connect the 3rd and 4th ventricle for CSF drainage

Question 6

What are the three endogenous opioids that have been discovered?

Answer 6

Enkaphalins - stimulate the delta opioid receptor and suppress pain

Endoprhins

Dynorphins

These are the three endogenous opioids

Question 7

How do morphine and their related compounds cause electrical excitation of the periaquedcutal grey matter?

Answer 7

The periaqueductal gray (PAG) is the primary control center for descending pain modulation. It has enkephalin-producing cells that suppress pain Morphine and their related compounds inhibit inhibitory GABAergic interneurones (disinhibition)

Question 8

What is the main opioid receptor known as? It is responsible for most of the analgesic actions of opioid but unfortunately has some major side effects such as what?

Answer 8

This is the mu opioid receptor - also known as MOP receptor (μ (mu, aka MOP)) Some of the major side effects however are respiratory depression, sedaton, constipation, euphoria, dependency

Question 9

Apart from the mu opioid receptor (MOP), κ (kappa, aka KOP) and δ (delta, aka DOP) opioid receptors exist Which receptor do opioid analgesics mainly work on? What side effects are associated with stimulation of kappa and delta opioid receptors?

Answer 9

This would be the mu opioid receptor (MOP) Kappa opioid receptors - associated with sedation, dysphoria and hallucinations Delta opioid receptors - are pro-convulsants if stimulated

Question 10

AGONISTS: as analgesics, act mainly through prolonged activation of μ-opioid receptors What is the widely used agonist in rung 3 of the WHO analgesic pain ladder? How can it be given?

Answer 10

This would be morphine Can be given IV, subcut, IM and oral for chronic pain

Question 11

What is the main opioid antagonist that is given? How does it work? When is it given?

Answer 11

The main opioid antagonist is nalaxone It works by inhibiting all the opioid receptors - MOP (mu), Kappa (KOP), Delta (DOP) but has its highest affinity for antagonsiing the MOP receptors It is given for the treatment of respiratory depression or other opioid toxicities

Question 12

Naloxone is used to reverse opioid toxicity (i.e. respiratory and/or neurological depression) associated with ‘strong opioid’ overdosage WHat are the different options for route of adminsitration of nalaxone? Does it have a long or short half life?

Answer 12

Can be given IV, IM or subcut - usually IV though It has a short half-life - very important clinically since opioid toxicity can recur to ‘strong opioid’ agonists with a longer duration of action

Question 13

What can nalaxone trigger in opioid addicts?

Answer 13

It can trigger withdrawal in patients who are opioid addicts eg heroin abusers

Question 14

If a patient has an opioid or heroin withdrawal, what can be given to alleviate the symptoms?

Answer 14

Can give lofexidine - it is an alpha 2 adrenegeric receptor agonist Lofexidine is an α2A adrenergic receptor agonist, historically used as an antihypertensive, but more commonly used to alleviate the physical symptoms of heroin and other types of opioid withdrawal

Question 15

What is the drug, similar to naloxone, but with the advantage of a much longer half-life?

Answer 15

Naltrexone - also an opioid antagonist

Question 16

NSAIDs, especially ibuprofen and naproxen, are very widely employed to reduce mild/moderate inflammatory pain. What do non selective NSAIDs inhibit? What do selective NSAIDs inhibt? What do selective NSAIDs prevent?

Answer 16

Non selective NSAIDs inhibit cyclooxygenase enzymes COX1 and COX2 Selective NSAIDs inhibit COX2 and therefore prevent GI toxicity which is mediated by inhibition of COX-1

Question 17

What are the three different effects of NSAIDs? What do the selective NSAIDs, COX 2 selective inhibitors, names all end with?

Answer 17

Analgesia, anti-inflammatory and anti-pyretic All end with coxib

Question 18

Why is paracetamol not classified as an NSAID?

Answer 18

It is not classified as an NSAID as it does not exhibit anti-inflammatory effects (only weakly inhibits COX enzymes) and therefore only has an anti pyretic and analgesic effect

Question 19

The analgesic effect of paracetamol is due to its metabolites. What is the main metabolite? It is this metabolite that is responsible for hepatoxicity in overdosage What is given for treatment of a paracetamol overdose?

Answer 19

N-acetyl-p-benozoquinoneimine (NAPBQI) NAPBQI is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol. It is normally produced only in small amounts, and then almost immediately detoxified in the liver. For paracetamol overdose - N-acetyl cystein is given as treatment

Question 20

Long term administration of non-selective NSAIDs may produce gastrointestinal damage (PGE2 produced by COX-1 protects against the acid/pepsin environment). Paracetamol does not have this adverse effect. Why are selective COX-2 inhibitors limited in their use?

Answer 20

This is because they are prothrombotic

Question 21

Neuropathic pain is severe and debilitating occurring in conditions such as: * trigeminal neuralgia * diabetic neuropathy * post-herpetic neuralgia * phantom limb pain What are the three main treatment options for neuropathic pain? What is their mechansim of action?

Answer 21

Trigeminal neuralgia - Carbamezapine 1st line, can try gabapentin or lamtorgiine or phenyotin 2nd line Carbamezapine - blocks voltage sensitive sodium channels * Gabapentin and pregablin - (GABA analogues but instead they) bind to voltage gated Ca2+ channels decreasing release of glutamate and subtance P * Tricylics - selectively decreases the reuptake of noradrenaline, also works on 5HT (serotonin) Any other neuropathic pain - amitriptyline, duloxetine, gabapentin, pregabalin