Pain Pharmacology

Question 1

What are the drugs for pain?

Answer 1

paracetamol
opioids
co-amoxiclav
lactulose

Question 2

What are the possible opioids for pain?

Answer 2

Weak – codeine, tramadol
Strong – morphine, fentanyl, (heroin)

Question 3

What is the drug target for paracetamol?

Answer 3

Unclear.
5HT3 receptors/Cannabinoid reuptake proteins/Peroxidase

Question 4

What is the mechanism of action for paracetamol?

Answer 4

Still not totally clear.

At peripheral sites, may inhibit a peroxidase enzyme which is involved in the conversion of arachidonic acid to prostaglandins (1st step in this pathway involves the enzyme, cyclooxygenase). The ability of paracetamol to inhibit peroxidase can be blocked if excessive levels of peroxide build up (as is commonly seen in inflammation)

Activation of descending serotonergic pathways possibly via 5HT3 receptor activation.

Inhibits reuptake of endogenous endocannabinoids, which would increase activation of cannabinoid receptors - this may contribute to activation of descending pathways.

Question 5

What are the main side effects of paracetamol?

Answer 5

Relatively safe drug with few common side effects.

OVERDOSE:
Liver damage and less frequently renal damage.

Nausea and vomiting early features of poisoning (settle in 24h).
Onset of right subcostal pain after 24h indicates hepatic necrosis.

Question 6

What are the an/antis of paracetamol?

Answer 6

Analgesic and anti-pyretic.

Does NOT possess anti-inflammatory activity

Question 7

What are the drug targets of opioids?

Answer 7

Opioid receptor

Question 8

What is the mechanism of action of opioids?

Answer 8

Over-arching mechanism at a cellular level is a depressant effect on cellular activity. Multiple sites within pain pathway, where activation of the opioid receptor leads to decreased perception or increased tolerance to pain.
Antitussive effect due to decreased activation of afferent nerves relaying cough stimulus from airways to brain

Question 9

What are the side effects of opioids?

Answer 9

Mild – nausea & vomiting (increase activity in chemoreceptor trigger zone) and constipation (opioid receptors in GIT can reduce gut motility)

OVERDOSE - respiratory depression (direct and indirect inhibition of respiratory control centre.)

Question 10

What are the drug targets of co-amoxiclav?

Answer 10

Amoxicillin = penicillin binding proteins
Clavulanate = beta lactamase

Question 11

What is the mechanism of action of co-amoxicillin?

Answer 11

Amoxicillin (like all penicillin like drugs) binds to bacterial penicillin binding proteins. This prevents transpeptidation (the cross linking process for bacterial cell wall synthesis)

Clavulanate is an inhibitor of beta lactamase. Beta lactamase is a bacterial enzyme that can degrade beta lactam anti-biotics and thus confer resistance to these anti-biotics.

Question 12

What are the side effects of co-amoxiclav?

Answer 12

Amoxicillin is well tolerated. Most common side effects are nausea and diarrhoea.

Question 13

What is amoxicillin?

Answer 13

Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms

Question 14

What is hypersensitivity of penicillin associated with?

Answer 14

rash but can lead to anaphylactic reactions

Question 15

What is the drug target of lactulose?

Answer 15

no drug target

Question 16

What is the mechanism of action of lactulose?

Answer 16

Lactulose is a non-absorbable disaccharide. It reaches the large bowel unchanged. This causes water retention via osmosis and an easier to pass stool. It can also be metabolised by colonic bacteria. The colonic metabolism of sugars has an additional laxative effect.

Question 17

What are the side effects of lactulose?

Answer 17

Abdominal pain, diarrhoea, flatulence, nausea.

Question 18

How long does it take for lactulose to work?

Answer 18

Begins working within 8-12 hours but may take up to 2 days to improve constipation.

Question 19

Why are lactulose and opioids commonly prescribed tgt (in a way)?

Answer 19

Constipation is a very common side effect of opioids. Lactulose is often prescribed prior to commencement of opioid therapy to improve symptoms associated with constipation.

Question 20

What is the patient’s problem?

Answer 20

Question 21

How would you give opioids dependent on pain?

Answer 21

WHO pain ladder

Question 22

What are the therapeutic objectives?

Answer 22

If diagnosed with gastroenteritis…

Oral rehydration: Can manage oral fluids, but is at risk of dehydration due to consistent diarrhea and vomiting

Analgesia: Complaining of abdominal pain. Over the counter paracetamol is fine (no need to prescribe)
Most patients can manage gastroenteritis at home.

Question 23

What is the treatment for this patient by the GP?

Answer 23

regular oral fluids and simple analgesia such as paracetamol

advised to stay off work for 48h and reminded of good hygiene to stop spread

told to seek advice if his symptoms persist, feels more unwell or has symptoms of dehydration?

Question 24

Describe the pain pathway.

Answer 24

• peripheral receptor activated by pain stimulus
• nerve signal travels from peripheral sensory neurone to dorsal horn of spinal cord
• peripheral sensory neuron synapse with spinothalamic neuron
• spinothalamic neuron travels up to thalamus
• thalamus sends signal to cerebral cortex
• cerebral cortex decides how much to activate downstream inhibitor pathway
• downstream pathway modulates the signal
• signal goes back down to dorsal horn and signal (from peripheral to thalamus) is diminished

Question 25

What is the difference between NSAIDs and paracetamol?

Answer 25

- both work by preventing release of prostaglandins - NSAIDs and paracetamol inhibit in different parts of the pathway

Question 26

3 days later, Mr Chow experiences a sudden worsening of his abdominal pain and presented to the Emergency Department. The pain progressively worsened over the preceding 2 hours and has moved to the right lower quadrant. On examination, he appears unwell. His temperature is 38.1°C, heart rate 112 bpm regular, blood pressure 108/68 mmHg. He is extremely tender in the right iliac fossa, with guarding and rebound tenderness. Bowel sounds are present. Chest examination and heart sounds are normal. His FBC shows a WCC of 14.2 x 109/l, and CRP of 89mg/l. He is given fluids, IV antibiotics, made nil by mouth, and is admitted under the surgical team. What is the patient's problem?

Answer 26

acute appendicitis

Question 27

3 days later, Mr Chow experiences a sudden worsening of his abdominal pain and presented to the Emergency Department. The pain progressively worsened over the preceding 2 hours and has moved to the right lower quadrant. On examination, he appears unwell. His temperature is 38.1°C, heart rate 112 bpm regular, blood pressure 108/68 mmHg. He is extremely tender in the right iliac fossa, with guarding and rebound tenderness. Bowel sounds are present. Chest examination and heart sounds are normal. His FBC shows a WCC of 14.2 x 109/l, and CRP of 89mg/l. He is given fluids, IV antibiotics, made nil by mouth, and is admitted under the surgical team. What are the therapeutic objectives?

Answer 27

Surgery – open laparoscopy Hydration (would need to be nil by mouth) – intravenous crystalloids Analgesia – move up the pain ladder as pain more intense Antibiotics – obstructed appendix could lead to bacterial overgrowth, plus risk of pos-surgical infection

Question 28

Mr Chow is admitted under the surgical team and made nil by mouth. He is given intravenous maintenance fluids as well as intravenous morphine (initially 5mg every 4 hours – dose adjusted based on response) and prophylactic antibiotics (intravenous co-amoxiclav -1.2g every 8h). Explain what effect morphine would have at a cellular level using the diagram provided.

Answer 28

- inhibit calcium from binding → prevents release of neurotransmitters - increases efflux of K+ → hyperpolarises the neuron - prevents conversion of ATP to cAMP → depressant effect on the cell

Question 29

What is the effect of morphine on the pain pathway?

Answer 29

- activates modulation pathway → increases the diminishment of pain pathway, by inhibiting the GABA receptors - inhibiting an inhibiting factor is called disinhibition - inhibits neurotransmission from peripheral sensory neurone to spinothalamic neurone - inhibits peripheral sensory neurone from picking up on pain signal

Question 30

In order for opioids (or any drugs) to produce effects within the brain, it needs to be able to access the brain tissue. The major route for drug permeation into the brain is via passive diffusion. Lipid solubility is the major determinant of passive diffusion. Once inside the brain, opioids need to bind to opioid receptors in order to produce any effect. In this case, it is the chemical structure of the drug that determines the ability to bind to the receptor. You have been provided with five different opioids below, with information on their structure and lipid solubility. Discuss the ability of each of these opioids to produce opioid like effects in the brain.

Answer 30

- a drug needs to be sufficient lipophilic AND have high affinity for receptor in order to be effective - lipophilic → the oil-water partition coefficient is between 1.5-2.7 - high affinity → OH group at position 3 AND tertiary nitrogen - 6-acetyl morphine is the only drug listed that is both lipophilic and has affinity to bind to receptor

Question 31

Following a successful appendicectomy, Mr Chow is returned to the ward with patient-controlled analgesia containing IV morphine. Later that day, Mr Chow is found unresponsive in his bed. An ABCDE assessment is done: A – Patent. B – Respiratory rate 6 breaths per minute, O2 sats 91%, chest is clear. C – Heart rate 48 bpm regular, BP 74/59 mmHg, heart sounds normal. D – Capillary blood glucose 4.7, AVPU unresponsive, pupils constricted bilaterally. E – Temperature 36.7°C, abdomen surgical wound appears clean. Mr Chow is suffering from opioid overdose. He is provided with ventilatory support (oxygen) and administered naloxone intravenously (0.5mg, repeat every 2 minutes with 0.2-0.4mg increments according to response). what classical signs of opioid overdose is Mr Chow presenting with?

Answer 31

* decreased resp rate bc inhibition of central system * constricted pupil - opioids activates occulomotor nerve bc of gaba disinhibitation → constricts pupils - VS in normal unresponsive patients pupils are dilated * urea and creatinine raised → acute renal failure - opioid overdose leads to rhabdomyolysis (breakdown of muscle tissue that releases muscle contents into blood → harmful to kidneys) - makes the overdose worse bc morphine cannot be cleared from body due to renal failure

Question 32

What is naloxone?

Answer 32

Morphine is an opioid receptor agonist. Naloxone is an opioid receptor antagonist. Agonists possess affinity and efficacy for a receptor. Antagonists only possess affinity for a receptor.

Question 33

Compare the structure of morphine and naloxone.

Answer 33

Naloxone is an example of an opioid antagonist that is synthesized by replacing the methyl group (CH3) on the nitrogen (N) found in the structure of morphine with an allyl group (CH2CH=CH2)

Question 34

As noted previously, codeine is primarily a pro-drug for morphine. As you can see in the figure below, codeine can be metabolized to both norcodeine (inactive metabolite) AND morphine (active metabolite). In the liver, cytochrome P450 enzymes are responsible for this metabolism. CYP3A4 is responsible for ‘fast’ metabolism of codeine to norcodeine and CYP2A6 is responsible for ‘slow’ metabolism of codeine to morphine. What do you think is the significance of this?

Answer 34

- conversion of codeine to norcodeine (inactive) is fast, and abt 90% of the reactions - conversion of codeine to morphine is slow, and abt 10% of the reactions - need to do the math to figure out how much codeine to actually give him, bc switching from morphine to codeine

Question 35

When would you give oral morphine (not IM), and how do you calculate dose?

Answer 35

still suffering on discharge with pain and thus would still need pain killers to treat this. He would need to switch from intravenous opioid treatment to an oral opioid. In this case from morphine to codeine. Morphine to codeine dose conversion... Divide the total daily dose of morphine by 0.1 to obtain an equivalent dose of codeine. Total morphine = 2.5 x 4 = 10 mg per day Morphine to codeine conversion = 10/0.1 = 100 mg codeine per day Codeine dose (given QDS) = 100/4 = 25mg per dose Equivalent codeine = 25mg QDS

Question 36

What should you normally do to the codeine dose?

Answer 36

It is generally recommended that the dose is reduced by 30% to reduce the risk of overdose. Hence 25mg x 0.7 = 17.5mg. - However, dose reduction may not be necessary in a young man like Mr Chow who has no other underlying medical conditions. In this case, no dose reduction was applied. Codeine comes in 15mg, 30mg and 60mg. Discharge TTA (to take away) = Codeine, 30mg, PO, QDS PRN