Pain management

Question 1

1) What is the main clinical use for opiates/ opioids?

2) What is the main clinical use for paracetamol and combination analgesics?

Answer 1

1) Acute and chronic moderate to severe pain, WHO pain ladder
2) Mild to moderate pain.

Question 2

Name the 5 opioid P drugs.

Answer 2

1) Codeine phosphate
2) Tramadol
3) Diamorphine
4) Morphine sulfate
5) Fentanyl (transdermal)

Question 3

Name 2 combination P drugs which are associated with paracetamol.

Answer 3

1) Co-codamol

2) Co-dydramol

Question 4

What is the main clinical use of NSAID analgesics?

Answer 4

Mild to moderate pain (chronic and neuropathic pain)

Question 5

Name the 2 P drugs which are NSAIDs.

Answer 5

1) Ibuprofen

2) Naproxen

Question 6

What is the main clinical use for non-opioid non-NSAID analgesics?

Answer 6

Chronic and neuropathic pain.

Question 7

Name the 4 P drugs which are non-opioid non-NSAID analgesics.

Answer 7

1) Amitriptyline
2) Carbamazepine
3) Capsaicin
4) Pregabalin

Question 8

Give the 4 main clinical indications for the use of gabapentin and pregabalin.

Answer 8

1) Focal epilepsies (both drugs) with or without secondary generalisation.
2) Both drugs are used for neuropathic pain.
3) Gabapentin is used in migraine prophylaxis.
4) Pregabalin is used in GAD.

Question 9

1) Describe how gabapentin/pregabalin are used with regards to epilepsy.
2) Which drug is recommended as a second line option in painful diabetic neuropathy (after duloxetine) and as a first line option in other painful neuropathies?
3) From a structural point of view, what is gabapentin closely related to?
4) What is pregabalin?

Answer 9

1) Usually as an add-on treatment when other anti- epileptic drugs such as carbamazepine provide inadequate control.
2) Pregabalin.
3) gamma-aminobutyric acid (GABA)
4) A structural analogue of gabapentin (so probably has a similar mechanism of action).

Question 10

Describe the basic mechanism of action of gabapentin.

Answer 10

Binds to voltage-sensitive Ca2+ channels > prevents inflow of calcium > inhibits neurotransmitter release > interferes with synaptic transmission > reduces neuronal excitability.

Question 11

1) Give the 3 main side effects of gabapentin and pregabalin.
2) How are gabapentin and pregabalin eliminated from the body?
3) In who should doses of gabapentin/pregabalin be reduced?

Answer 11

1) Drowsiness, dizziness, ataxia.
2) By the kidneys.
3) In those with renal impairment.

Question 12

1) When might the sedative effects of gabapentin and pregabalin be enhanced?
2) Why are gabapentin and pregabalin particularly useful when combination regimens for epilepsy are considered necessary?

Answer 12

1) When combined with other sedating drugs.

2) Because they have relatively few drug interactions compared with most other antiepileptic drugs.

Question 13

1) How are gabapentin and pregabalin administrated?
2) How should gabapentin and pregabalin be started in order to improve tolerability?
3) How is the drug regimen then altered after the initial dosing?

Answer 13

1) Orally.
2) They should be started at a low dose.
3) The dose should be increased over subsequent days and weeks in order to reach a dose that strike the optimal balance between benefits and side effects.

Question 14

1) What is the best guide to clinical effectiveness for gabapentin and pregabalin?
2) If a patient is taking gabapentin and needs a urine dipstick, why does the sample also need to be sent to the lab for quantitive analysis.

Answer 14

1) To enquire about symptoms and side effects.

2) Because gabapentin may cause false positive results for detection of protein on urine dipstick testing.

Question 15

1) What is paracetamol a first line analgesic for?
2) How is paracetamol described on the WHO pain ladder?
3) Aside from use as an analgesic what is another clinical indication for the use of paracetamol?

Answer 15

1) Most forms of acute and chronic pain.
2) It is the basis of treatment with weak and then strong opioids added incrementally until pain is controlled.
3) Paracetamol is also used as an antipyretic that can reduce fever and its associated symptoms.

Question 16

1) What is paracetamol an inhibitor of?
2) What does COX inhibition appear to do in the CNS?
3) Which enzyme does paracetamol have specificity for?

Answer 16

1) It is a weak inhibitor of cyclooxyrgenase enzymes which are involved in prostaglandin metabolism.
2) COX inhibition appears to increase the pain threshold and reduce prostaglandin (PGE2) concentrations in the thermoregulatory region of the hypothalamus, controlling fever.
3) COX-2.

Question 17

1) When is the COX-2 isoform of the enzyme induced?
2) What is the COX-1 isoform of the isoenzyme involved in?
3) Why is paracetamol a weak anti-inflammatory?

Answer 17

1) In inflammation.
2) Protecting the gastric mucosa and regulating renal blood flow and clotting.
3) Because its actions are inhibited in inflammatory lesions by the presence of peroxides.

Question 18

1) Describe the side effect pattern of paracetamol at low treatment doses.
2) Why does paracetamol not cause peptic ulceration, renal impairment or precipitation of CV events like NSAIDs do?
3) What does paracetamol cause in overdose?

Answer 18

1) At treatment doses, paracetamol is very safe with few side effects.
2) Because there is lack of inhibition of COX-1 with paracetamol.
3) Liver failure.

Question 19

1) What is paracetamol metabolised by?
2) What is paracetamol metabolised to?
3) What is the metabolic product of paracetamol conjugated with before elimination?

Answer 19

1) CYP450 enzymes.
2) A toxic metabolite (NAPQI)
3) NAPQI is conjugated with glutathione before elimination.

Question 20

1) What happens to the elimination pathway of paracetamol in overdose?
2) What happens to the liver because of this?
3) How is hepatotoxicity treated in paracetamol overdose?

Answer 20

1) It becomes saturated.
2) NAPQI accumulation causes hepatocellular necrosis.
3) Hepatotoxicity in paracetamol overdose is treated by acetylcysteine.

Question 21

1) In who should doses of paracetamol be reduced?

2) When is dose reduction of paracetamol in these scenarios particularly important?

Answer 21

1) In people at increased risk of liver toxicity either because of increased NAPQI production (chronic excessive alcohol use - induces enzymes) or reduced glutathione stores (malnutrition, low body weight, severe hepatic impairment).
2) Dose reduction in people at increased risk of liver failure is particularly important where paracetamol is given by IV infusion.

Question 22

Describe the only notable clinically significant drug interaction of paracetamol.

Answer 22

CYP450 inducers (e.g. phenytoin and carbamazepine) increase the rate of NAPQI production, causing an increased risk of liver toxicity after paracetamol overdose.

Question 23

1) Give 3 ways that paracetamol can be administered.
2) What is the usual adult dose of paracetamol for all routes of administration?
3) When paracetamol is prescribed under an ‘as required’ regimen, what other information must also be stated on the prescription?

Answer 23

1) Orally, IV, rectally.
2) 0.5-1g every 4-6 hours with a maximum dose of 4g daily.
3) The maximum daily dose must also be stated.

Question 24

After paracetamol overdose, what tests are required in order to establish the efficacy of acetylcysteine and to determine the need for further treatment?

Answer 24

INR, serum alanine aminotransferase (ALT) and creatinine concentration.

Question 25

Why should IV paracetamol be reserved for those unable to take medicines by mouth and why should administration be switched from IV to oral as soon as possible?

Answer 25

Because IV paracetamol is about 60 times more expensive than oral formulations of paracetamol.

Question 26

Give the 4 main clinical indications for the use of strong opioids.

Answer 26

1) Rapid relief of acute severe pain (incl. post operative pain and pain associated with MI).
2) For relief of chronic pain (when paracetamol, NSAIDs and weak opioids are insufficient).
3) For relief of breathlessness in the context of end of life care.
4) To relieve breathlessness and anxiety in acute pulmonary oedema, alongside oxygen, furosemide and nitrates.

Question 27

1) Name 2 examples of strong opioids.

2) How does the therapeutic action of opioids arise?

Answer 27

1) Morphine (naturally occurring) and oxycodone (synthetic analogue).
2) From activation of mu opioid receptors in the CNS.

Question 28

1) What type of receptor are mu opioid receptors?

2) What are the overall effects of activation of these receptors?

Answer 28

1) They are G-protein coupled receptors.
2) Activation of G-protein coupled receptors has several effects which overall reduce neuronal excitability and pain transmission.

Question 29

1) What do opioids do in the medulla?
2) By relieving pain, breathlessness and associated anxiety, what do opioids reduce?
2a) Therefore, in MI and acute pulmonary oedema what might opioids reduce which will be beneficial?
3) What is one problem with the use of morphine in acute pulmonary oedema?

Answer 29

1) In the medulla, they blunt the response to hypoxia and hypercapnoea which reduces respiratory drive and breathlessness.
2) They reduce sympathetic nervous system activity.
2a) They may reduce cardiac work and oxygen demand, as well as relieving symptoms.
3) Although it is commonly used, the efficacy and safety of morphine in acute pulmonary oedema is not firmly established.

Question 30

1) What do opioids cause through reduction of the respiratory drive?
2) Opioids can cause euphoria and detachment, as well as what in higher doses?
3) Why can opioids cause nausea and vomiting?
4) Why does pupillary constriction occur when opioids are used?

Answer 30

1) Respiratory depression.
2) They can cause neurological depression in higher doses.
3) Because they can activate the chemoreceptor trigger zone.
4) Due to stimulation of the Edinger-Westphal nucleus .

Question 31

1) How do opioids cause constipation?
2) In the skin, opioids may cause histamine release which can lead to what 4 effects?
3) What can continued long term use of opioids lead to?
4) When would dependence on opioids become apparent?

Answer 31

1) In the large intestine, activation of mu receptors increases smooth muscle tone and reduces motility leading to constipation.
2) itching, urticaria, vasodilatation and sweating.
3) Tolerance and dependence.
4) Upon cessation of the opioid when a withdrawal reaction occurs.

Question 32

What is tolerance?

Answer 32

A state in which the dose required to produce the same effect increases over time.

Question 33

1) In who should doses of opioids be reduced and why?
2) When should you NOT prescribe opioids?
3) Why should opioid use be avoided in biliary colic?

Answer 33

1) Those with hepatic failure/ renal impairment and the elderly because most opioids rely on the liver and kidneys for elimination.
2) In respiratory failure (except under senior guidance such as in palliative care).
3) Because they may cause spasm of the sphincter of Oddi which could worsen the pain.

Question 34

1) What drugs should opioids ideally not be used with?

2) If combination of these drugs is unavoidable, what is necessary?

Answer 34

1) Other sedating drugs (e.g. antipsychotics, BDZs and TCAs).
2) Close monitoring is necessary.

Question 35

1) When treating acute, severe pain in high dependency areas, how is morphine given?
2) What is the usual initial dose of IV morphine?
3) For chronic pain, what route of administration of morphine is safest and usually most appropriate?

Answer 35

1) IV for rapid effect (onset at about 5 minutes).
2) 2-10mg tailored to pain, age and other individual factors, prescribed in the once only section.
3) Oral.

Question 36

Describe the regimen for prescribing oral morphine.

Answer 36

Immediate release oral morphine is preferred initially (e.g. Oramorph 5mg every 4 hours). Then, once the optimum dose is found, convert to a modified release form (e.g. MST Continus 15mg every 12 hours).

Question 37

Alongside regular morphine treatment, what should also be prescribed?

Answer 37

Breakthrough analgesia should also be prescribed (immediate release morphine at a dose of about one sixth of the total daily regular dose, for example, Oramorph 5mg 2 hourly). This should be prescribed in the as required section.

Question 38

1) What are the clinical features of opioid withdrawal the opposite to?
2) Describe the features of opioid withdrawal.
3) When does opioid dependence tend to be less problematic?

Answer 38

1) The clinical effects of opioids.
2) Anxiety, pain, breathlessness, pupil dilation, cool and dry skin with pilo-erection (‘cold turkey’).
3) When opioids are taken therapeutically rather than recreationally (although, do not let this deter you from offering opioids for severe or chronic pain, especially in end of life care).

Question 39

1) For safety, how should strong oral opioids be prescribed?
2) Why should IV morphine only be given in high dependency areas?
3) Morphine should be given incrementally (i.e. 1-2mg every few minutes) in order to achieve what?

Answer 39

1) Brand name prescribing should be used for strong oral opioids.
2) Because when given via the IV route, adverse effects may be more pronounced.
3) The desired response.

Question 40

Give the main common clinical indication for the use of weak opioids.

Answer 40

For mild to moderate pain, including post-operative pain as second line agents when simple analgesics such as paracetamol are insufficient.

Question 41

1) Where are weak opioids situated on the WHO pain ladder?
2) Name 3 weak opioids.
3) What are codeine and dihydrocodeine metabolised into by the liver?

Answer 41

1) They are on the second rung of the WHO pain ladder.
2) Codeine, dihydrocodeine and tramadol.
3) Codeine is metabolised into morphine and dihydrocodeine is metabolised into dihydromorphine.

Question 42

1) Name 4 common side effects of weak opioids.
2) What 2 things can all opioids cause when taken in overdose?
3) Why must codeine and dihydrocodeine never be given intravenously?

Answer 42

1) Nausea, constipation, dizziness and drowsiness.
2) Neurological and respiratory depression.
3) Because this can cause a severe reaction similar to anaphylaxis which is mediated by histamine release but does not have an ‘allergic’ basis.

Question 43

1) When should caution be exercised when prescribing an opioid?
2) In whom should weak opioids be prescribed at a reduced dose in?
3) Why is tramadol best avoided in patients with epilepsy?
4) In who should tramadol absolutely not be used in?

Answer 43

1) In the context of significant respiratory disease.
2) Those with renal/ hepatic impairment and the elderly.
3) Because it lowers the seizure threshold.
4) Those with uncontrolled epilepsy.

Question 44

1) Where is the use of IM opioids largely restricted to?
2) Whenever you prescribe an opioid for regular administration, what else should you consider prescribing?
3) What is a common starting prescription for codeine/ dihydrocodeine?
4) What is a common starting prescription for tramadol?

Answer 44

1) Operating theatres.
2) A laxative (a stimulant laxative such as Senna is a reasonable choice).
3) 30mg orally 4 hourly.
4) 50mg orally 4 hourly.

Question 45

1) Describe how anaesthetists could use IM codeine.

2) Name the main side effect of IM injection of codeine.

Answer 45

1) While the patient is still under general anaesthesia in order to provide post-operative analgesia.
2) Formation of a red patch at the injection site which is mediated by histamine release. Provided this patch is not progressive, there is no cause for alarm.

Question 46

Give the 2 common clinical indications for the use of NSAIDs.

Answer 46

1) ‘As needed’ treatment of mild to moderate pain (dysmenorrhoea, dental pain) as an alternative or in addition to paracetamol.
2) Regular treatment for pain related to inflammation, particularly of MSK system.

Question 47

1) If use of NSAIDS in patients at high risk of adverse events is unavoidable, how should they be prescribed?
2) Describe the interaction between NSAIDs and Warfarin.
3) Describe the interaction between NSAIDs and antihypertensives/ diuretics.

Answer 47

1) Should prescribe the safest NSAID at the lowest effective dose for the shortest possible time.
2) NSAIDs increase the risk of bleeding with warfarin.
3) NSAIDs reduce the therapeutic effects of antihypertensives and diuretics.

Question 48

1) What do NSAIDs do?
2) What does COX-1 do?
3) What does COX-2 do?
4) What 3 functions are prostaglandins essential for?

Answer 48

1) Inhibit synthesis of prostaglandins from arachidonic acid by inhibiting cyclooxyrgenase enzymes.
2) Constitutive form which stimulates prostaglandin synthesis.
3) Inducible form which is expressed in response to inflammatory stimuli.
4) Preservation of the integrity of the gastric mucosa, maintaining renal perfusion (by dilating afferent glomerular arterioles) and inhibition of thrombus formation at the vascular endothelium.

Question 49

1) What are the therapeutic effects of NSAIDs generally mediated by?
2) What are the adverse effects of NSAIDs generally mediated by?
3) Why were selective COX-2 inhibitors developed? Give an example.

Answer 49

1) COX-2 inhibition.
2) COX-1 inhibition.
3) In an attempt to reduce adverse effects of NSAIDs. An example of a COX-2 inhibitor is Etoricoxib.

Question 50

1) Name the 3 main categories of adverse effects of NSAIDs.
2) Which NSAID is associated with the lowest risk of GI adverse events?
3) Which NSAIDs are associated with the lowest risk of CV adverse events?

Answer 50

1) GI toxicity, renal impairment and increased risk of CV events (MI and stroke).
2) Ibuprofen is associated with the lowest risk of GI effects.
3) Naproxen and low-dose ibuprofen are associated with the lowest risk of CV events.

Question 51

1) Give the advantage and disadvantage associated with COX-2 inhibitors.
2) Name 2 other non-categorised adverse effects of NSAIDs.
3) What can all types NSAIDs cause (selective and non-selective)?

Answer 51

1) COX-2 inhibitors cause fewer GI side effects than non-selective NSAIDs, but are associated with an increased risk of CV events.
2) Hypersensitivity reactions (e.g. bronchospasm and angioedema) and fluid retention (can worsen HTN and HF).
3) Renal impairment.

Question 52

1) How are NSAIDs generally administered?
2) Name 3 other methods of administration of NSAIDs.
3) What should oral NSAIDs be taken with in order to minimise GI upset?

Answer 52

1) Orally.
2) Topical gels, suppositories, injectable preparations.
3) Food.

Question 53

1) If a patient experiences indigestion with NSAIDs, what should you advise them to do?
2) What should you advise patients requiring long term NSAID treatment to do if they become acutely unwell or dehydrated (particularly if they have renal impairment)?
3) What should be considered for all patients taking NSAIDs who are at an increased risk of GI complications?

Answer 53

1) Stop the drug and seek medical advice.
2) Stop the drug in order to reduce the risk of damage to the kidneys.
3) Gastroprotection (e.g. PPI).

Question 54

Describe the first step on the WHO pain relief ladder.

Answer 54

Non-opioid ± adjuvant.

Question 55

Describe step 2 on the WHO pain relief ladder.

Answer 55

Opioid for mild to moderate pain ± non-opioid ± adjuvant.

Question 56

Describe step 3 on the WHO pain relief ladder.

Answer 56

Opioid for moderate to severe pain ± non-opioid ± adjuvant.

Question 57

1) When is it appropriate to step up on the WHO pain management ladder?
2) What is meant by ‘adjuvants’ on the WHO pain ladder?
3) In order to maintain freedom from pain, under what regimen should pain medication be given?
4) What method of management might be used if drugs are proving ineffective for pain management?

Answer 57

1) If pain is increasing or persisting despite treatment.
2) Adjuvant drugs used involve those used to calm fears and anxiety.
3) Pain drugs should be given ‘by the clock’ (every 3-6 hours) rather than ‘on demand’.
4) Surgical intervention on appropriate nerves may provide further pain relief if drugs are not wholly effective.

Question 58

What does the ‘3 step approach’ to pain management mean?

Answer 58

Administering the right drug, in the right dose, at the right time.