Pain

Question 1

Aspirin

Common indications

Answer 1

1. ACS and acute ischaemic stroke- where rapid inhibition of platelet aggregation can prevent or limit arterial thrombosis and reduce subsequent mortality
2. For long-term secondary prevention of thrombotic arterial events in patients with CV, cerebrovascular and peripheral arterial disease
3. To reduce the risk of intracardiac thrombus and embolic stroke in AF where warfarin and NOACs are contraindicated
4. Control mild-to-moderate pain and fever- although other drugs are usually

Question 2

Aspirin

MOA

Answer 2

• Thrombotic events occur when platelet-rich thrombus forms in atheromatous arteries and occludes the circulation
• Aspirin irreversibly inhibits cyclooxygenase (COX) to reduce the production of pro-aggregatory factor thromboxane from arachidonic acid, reducing platelet aggregation.
• Anti-platelet effect occurs at a low dose (75mg) and lasts for the lifetime of the platelet (~10days)

Question 3

Aspirin

Adverse effects

Answer 3

• The most common adverse effect of aspirin is gastrointestinal irritation.
• More serious effects include gastrointestinal ulceration and haemorrhage and hypersensitivity reactions, including bronchospasm.
• In regular high-dose therapy, aspirin causes tinnitus. Aspirin is life-threatening in overdose. Features include hyperventilation, hearing changes, metabolic acidosis and confusion, followed by convulsions, cardiovascular collapse and respiratory arrest.

Question 4

Aspirin

Warnings

Answer 4

• Aspirin should not be given to children aged under 16 years due to the risk of Reye’s syndrome, a rare but life-threatening illness that principally affects the liver and brain.
• It should not be taken by people with aspirin hypersensitivity, i.e. who have had bronchospasm or other allergic symptoms triggered by exposure to aspirin or another NSAID.
• However, aspirin is not routinely contraindicated in asthma.
• Aspirin should be avoided in the third trimester of pregnancy when prostaglandin inhibition may lead to premature closure of the ductus arteriosus.
• Aspirin should be used with caution in people with peptic ulceration (e.g. prescribe gastroprotection) or gout, as it may trigger an acute attack.

Question 5

Aspirin

Important interactions

Answer 5

• Aspirin acts synergistically with other antiplatelet agents, which although therapeutically beneficial can lead to an increased risk of bleeding. Therefore it is given with other antiplatelet and anticoagulants caution should still be used

Question 6

Aspirin

Communication

Answer 6

• Advise prescriber that this should be given with gastroprotection
• Advise patients that the purpose of low-dose aspirin is to prevent MI or stroke and prolong life
• Warn them about bleeding (mainly GI) and indegestion

Question 7

NSAIDs

Common indications

Answer 7

1. Mild-to-moderate pain as an addition to paracetamol
2. Pain-related to inflammation particularly- musculoskeletal (RA, OA and acute gout)

• Dosing in children
  
  • 1 month-5 months- 5mg/kg (Max 30mg/kg/day this is the same up to 4-6yrs)
  • 6month - 11 month- 50mg 3-4 times per day
  • 4-6yrs- 100mg tds
  • 7-9yrs 200mg tds (Max 2.4g daily )
  • 10-11- 300mg tds (Max 2.4g daily)
  • 12-17 300-400mg td-qd (up to 600mg qd if necessary)

Question 8

NSAID

MOA

Answer 8

• NSAIDs inhibit the synthesis of prostaglandins from arachidonic acid by inhibiting cyclooxygenase (COX).
• COX exists as two main isoforms. COX-1 is the constitutive form. It stimulates prostaglandin synthesis that is essential to preserve the integrity of the gastric mucosa; maintain renal perfusion (by dilating afferent glomerular arterioles), and inhibit thrombus formation at the vascular endothelium.
• COX-2 is the inducible form, expressed in response to inflammatory stimuli. It stimulates the production of prostaglandins that cause inflammation and pain.
• NSAIDs’ therapeutic benefits are principally mediated by COX-2 inhibition and adverse effects by COX-1 inhibition, although there is some overlap between the two. Selective COX-2 inhibitors (e.g. etoricoxib) were developed to reduce the adverse effects of NSAIDs.

Question 9

NSAID

Important adverse effects

Answer 9

• The main adverse effects of NSAIDs are gastrointestinal (GI) toxicity, renal impairment and increased risk of cardiovascular (CV) events (e.g. myocardial infarction and stroke).
• The likelihood of adverse effects differs between NSAIDs. Of all the non-selective NSAIDs (>20 are available), ibuprofen is associated with the lowest risk of GI effects.
• Naproxen and low-dose ibuprofen are associated with the lowest risk of CV events. COX-2 inhibitors cause fewer GI side effects than non-selective NSAIDs but are associated with an increased risk of CV events.
• All NSAIDs, including COX-2 inhibitors, can cause renal impairment. Other adverse effects include hypersensitivity reactions, e.g. bronchospasm and angioedema, and fluid retention, which can worsen hypertension and heart failure.

Question 10

NSAIDs

warnings

Answer 10

• Avoid NSAIDs in severe renal impairment, heart failure, liver failure and known NSAID hypersensitivity.
• If NSAID use is unavoidable in patients at high risk of adverse effects (e.g. prior peptic ulcer disease or GI bleeding, cardiovascular disease, renal impairment), use the safest NSAID at the lowest effective dose for the shortest possible time.

Question 11

NSAIDs

Interactions

Answer 11

• Many drugs increase the risk of NSAID-related adverse effects including GI ulceration: low-dose aspirin, corticosteroids; GI bleeding: anticoagulants, SSRIs, venlafaxine; renal impairment: ACE inhibitors, diuretics. NSAIDs increase the risk of bleeding with warfarin and reduce the therapeutic effects of antihypertensives and diuretics.

Question 12

NSAIDs

Communication

Answer 12

• Explain you are recommending an anti-inflammatory drug to help improve symptoms of pain, swelling and/or fever.
• Warn patients that the most common side effect is indigestion and advise them to stop treatment and seek medical advice if this occurs.
• For patients with acute pain, explain that long-term use, e.g. beyond 10 days, is not recommended due to the risk of side effects.
• Advise patients requiring long-term treatment (particularly if they have renal impairment) to stop NSAIDs if they become acutely unwell or dehydrated to reduce the risk of damage to the kidneys.

Question 13

Strong Opioids

Common indications

Answer 13

1. Acute severe pain- including post-operative and pain associated with MI
2. Chronic pain- when paracetamol, NSAIDs or weak opioids are insufficient
3. Breathlessness in the context of the end of life care
4. Relieve breathlessness and anxiety in acute pulmonary oedema, alongside O2, furosemide and nitrates

Question 14

Strong opioids

MOA

Answer 14

• The therapeutic action of opioids arises from activation of opioid μ (mu) receptors in the central nervous system.
• Activation of these G protein-coupled receptors has several effects that, overall, reduce neuronal excitability and pain transmission.
• In the medulla, they blunt the response to hypoxia and hypercapnia, reducing respiratory drive and breathlessness.
• By relieving pain, breathlessness and associated anxiety, opioids reduce sympathetic nervous system (fight or flight) activity. Thus, in myocardial infarction and acute pulmonary oedema, they may reduce cardiac work and oxygen demand, as well as relieving symptoms.
• That said, although commonly used, the efficacy and safety of morphine in acute pulmonary oedema is not firmly established.

Question 15

Strong opioids

Adverse effects

Answer 15

• Opioids cause respiratory depression by reducing respiratory drive. They may cause euphoria and detachment, and in higher doses, neurological depression.
• They can activate the chemoreceptor trigger zone, causing nausea and vomiting, although this tends to settle with continued use.
• Pupillary constriction occurs due to stimulation of the Edinger–Westphal nucleus.
• In the large intestine, activation of μ receptors increases smooth muscle tone and reduces motility leading to constipation.
• In the skin, opioids may cause histamine release, leading to itching, urticaria, vasodilatation and sweating.
• Continued use can lead to tolerance (a state in which the dose required to produce the same effect increases over time) and dependence.
• Dependence becomes apparent on cessation of the opioid when a withdrawal reaction occurs

Question 16

Strong opioids

Warnings

Answer 16

• Most opioids rely on the liver and kidneys for elimination, so doses should be reduced in hepatic and renal failure and in the elderly
• Do not give opioids in respiratory failure except under senior guidance (e.g. palliative care)
• Avoid opioids in biliary colic, as they may cause spasm of the sphincter of oddi, which can worsen pain

Question 17

Strong opioids

Interactions

Answer 17

• Opiods should ideally not be used with other sedating drugs (e.g. antipsychotics, BZs, TCA)
• Where their combination is unavoidable, close monitoring is necessary

Question 18

Strong opioids
Communication

Answer 18

• Patients may be reluctant to accept morphine, due to the stigma associated with abuse and dependence.
• Explain that it is a highly effective painkiller and that ‘addiction’ is not an issue when it is used for pain control.
• That said, you should warn patients that the dose may need to be increased over time as they become tolerant to its effects; this is normal and should not cause alarm.
• Explain how the patient should take their morphine: e.g. to take ‘slow-release’ tablets every 12 hours for background pain and use ‘fast-acting’ solution when required for breakthrough pain.
• Explain that nausea usually settles after a few days, but offer an antiemetic (e.g. metoclopramide). Constipation is very common; pre-emptive use of a laxative (e.g. senna), along with good hydration, is advisable. Advise patients not to drive or operate heavy machinery if they feel drowsy or confused.

Question 19

Weak opioids

Common indications

Answer 19

• Mild to moderate pain

Question 20

Weak opioids

MOA

Answer 20

• In unmodified form, codeine and dihydrocodeine are very weak opioids. They are metabolised in the liver to produce relatively small amounts of morphine (from codeine) or dihydromorphine (from dihydrocodeine).
• These metabolites, which are stronger agonists of opioid μ (mu) receptors (see Opioids, strong), probably account for most analgesic effect.
• About 10% of Caucasians have a less active form of the key metabolising enzyme (CYP 2D6), and these people may find codeine and dihydrocodeine largely ineffective. T
• tramadol is a synthetic analogue of codeine; it is perhaps best classified as a ‘moderate’ strength opioid. Like codeine, tramadol and its active metabolite are μ-receptor agonists. Unlike other opioids, tramadol also affects serotonergic and adrenergic pathways, where it is thought to act as a serotonin and noradrenaline reuptake inhibitor. This probably contributes to its analgesic effect.

Question 21

Weak opioids

Adverse effects

Answer 21

• Common side effects of weak opioids include nausea, constipation, dizziness and drowsiness.
• All opioids can cause neurological and respiratory depression when taken in overdose.
• Tramadol may cause less constipation and respiratory depression than other opioids.
• Codeine and dihydrocodeine must never be given intravenously, as this can cause a severe reaction similar to anaphylaxis. This is mediated by histamine release but does not have an ‘allergic’ basis.

Question 22

Weak opioids

Warnings

Answer 22

• Caution must be exercised when prescribing an opioid in the context of significant respiratory disease
• Tramadol, codeine and dihydrocodeine, rely on both liver and kidneys for their elimination
• Doses should therefore be reduced in renal impairment and hepatic impairment, and also in the elderly
• Tramadol lowers the seizure threshold so is best avoided in patients with epilepsy, and certainly should not bed used in those with uncontrolled epilepsy

Question 23

Weak opioids

Interactions

Answer 23

• Opioids should ideally not be used with other sedating drugs (e.g. antipsychotics, BZs, TCA)
• Where their combination is unavoidable, closer monitoring is necessary
• Tramadol should not be used with other drugs that lower seizure threshold, such as SSRI and TCA

Question 24

Paracetamol

Common indications

Answer 24

1. Acute and chronic pain
2. Fever

• Dosing in children
  
  • neonate 15mg/kg
  • 1-2 months - 30-60mg every 8hrs (Max 60mg/kg/day)
  • 3-5months 60mg every 4-6hrs (Max 4 doses)
  • 6-23 months- 120mg every 4-6hrs
  • 2-3yrs 180mg every 4-6 hrs
  • 4-5years- 240mg every 4-6 hrs
  • 6-7yrs 240-250mg every 4-6hrs
  • 8-9yrs- 360mg-375mg every 4-6 hrs
  • 10-11yrs 480mg-500mg every 4-6hrs
  • 12-15 years 480-750mg every 4-6hrs
  • 16-17 yrs- 0.5-1g every 4-6hrs

Question 25

Paracetamol

MOA

Answer 25

• The mechanisms of action of paracetamol are poorly understood. Paracetamol is a weak inhibitor of cyclooxygenase (COX), the enzyme involved in prostaglandin metabolism.
• In the central nervous system, COX inhibition appears to increase the pain threshold and reduce prostaglandin (PGE2) concentrations in the thermoregulatory region of the hypothalamus, controlling fever.
• Paracetamol has specificity for COX-2 (the isoform induced in inflammation) rather than COX-1 (the isoform involved in protecting the gastric mucosa and regulating renal blood flow and clotting).
• However, despite its COX-2 selectivity, paracetamol is a weak anti-inflammatory, as its actions are inhibited in inflammatory lesions by the presence of peroxides.

Question 26

Paracetamol

Adverse effects

Answer 26

• At treatment doses, paracetamol is very safe with few side effects. Lack of COX-1 inhibition means that it does not cause peptic ulceration or renal impairment or precipitate cardiovascular events (unlike NSAIDs).
• Its safety makes it a popular choice as a first-line analgesic. In overdose, paracetamol causes liver failure.
• Paracetamol is metabolised by CYP to a toxic metabolite (N-acetyl-p-benzoquinone imine [NAPQI]), which is conjugated with glutathione before elimination.
• After an overdose, this elimination pathway is saturated, and NAPQI accumulation causes hepatocellular necrosis.
• Hepatotoxicity can be prevented by treatment with the glutathione precursor acetylcysteine.

Question 27

Paracetamol

Warnings

Answer 27

• Paracetamol dose should be reduced in people at increased risk of liver toxicity, either because of increased NAPQI production (e.g. chronic excessive alcohol use) Or reduced glutathione stores (e.g. malnutrition, low body weight and severe hepatic impairment)
• This is particularly important where paracetamol is given by iV infusion

Question 28

Paracetamol

Interactions

Answer 28

• CYP inducers increase the rate of NAPQI production and risk of liver toxicity after paracetamol overdose