MSK - Drugs for Muscle Pain (including NSAIDs revision)

Question 1

Compare and contrast the clinical actions of aspirin and ibuprofen.

Answer 1

Both aspirin and ibuprofen are:

(1) Anti-inflammatory
(2) Analgesic
(3) Antipyretic

Aspirin but NOT ibuprofen is an irreversible cyclo-oxygenase (COX) inhibitor and so a potent:
(4) Anti-platelet

Question 2

What would be the usual analgesic choice for a child with mild to moderate pain?

Answer 2

Paracetamol would usually be the preferred first choice. Ibuprofen may be considered if greater anti-inflammatory action and analgesia is required.

Question 3

Why does indometacin have a stronger anti-inflammatory profile than other nonselective NSAIDs?

Answer 3

Besides being a non-selective inhibitor of cyclo-oxygenase (COX), indometacin also inhibits phospholipase A2. Thus, indometacin reduces the production of leukotrienes, in addition to prostanoids, and so has a broader spectrum anti-inflammatory effect.

Question 4

Which form of cyclo-oxygenase is expressed in inflammatory cells at sites of acute inflammation.

Answer 4

Inducible cyclo-oxygenase-2 (COX-2)

Question 5

Why should etoricoxib be used with caution in a patient with active peptic ulcers?

Answer 5

Etoricoxib will impair wound healing and so pre-existing peptic ulcers are likely to persist.

Question 6

What is the MOST common adverse effect of paracetamol at clinical analgesic doses?

Answer 6

Nausea

Question 7

List THREE NSAIDs with greater selectivity for cyclo-oxygenase-2 (COX-2) over COX-1.

Answer 7

Etoricoxib, parecoxib (pro-drug of valdecoxib), celecoxib, meloxicam, mefenamic acid

Question 8

Which NSAID has the greatest risk of precipitating an asthma attack in a patient with NSAID exacerbated respiratory disease (NERD)?

Answer 8

Aspirin because it is an irreversible inhibitor of cyclo-oxygenase (COX)

Question 9

Which NSAIDs has the strongest anti-platelet effect?

Answer 9

Aspirin because it is an irreversible inhibitor of cyclo-oxygenase (COX)

Question 10

What is the MOST common adverse effect of non-selective NSAIDs?

Answer 10

Nausea and other gastrointestinal adverse effects

Question 11

What is the normal function of prostaglandins in the stomach?

Answer 11

Protective effects:
(1) Increase bicarbonate secretion
(2) Increase mucus secretion
(3) Increase blood flow to mucosa
(4) Decrease acid secretion

Question 12

Why do NSAID-induced pseudoallergic reactions occur?

Answer 12

Inhibition of cyclo-oxygenase (COX) causes shunting of arachidonic acid to overflow into the 5-lipoxygenase pathway for the production of leukotrienes. Leukotrienes activate cysteinyl leukotriene receptors promoting mast cell degranulation and allergic responses.

Question 13

At analgesic doses, what do ALL NSAIDs have in common?

Answer 13

At analgesic doses, all NSAIDs inhibit cyclo-oxygenase-2 (COX-2)

Question 14

For what severity of pain are NSAIDs useful as analgesics?

Answer 14

NSAIDs are only useful for analgesics for mild to moderate pain. NSAIDs have an analgesic ceiling as they work as analgesics by preventing prostaglandin-mediated sensitisation of nociceptive fibres.

Question 15

Explain why diclofenac is useful for the management of joint pain and inflammation.

Answer 15

Diclofenac accumulates in synovial fluid enabling a prolonged analgesic and anti-inflammatory at the joints while it has a relatively short plasma half-life and so fewer gastrointestinal adverse effects than other non-selective COX inhibitors.

Question 16

Why are ALL NSAIDs contraindicated in late pregnancy?

Answer 16

All NSAIDs inhibit cyclo-oxygenase-2 (COX-2) at analgesic and anti-inflammatory doses. Inhibition of COX-2 risks premature closure of the ductus arteriosus. All NSAIDs are therefore contraindicated in the third trimester.

Question 17

Which form of cyclo-oxygenase (COX) do platelets predominantly express?

Answer 17

Platelets express cyclo-oxygenase-1 (COX-1) which makes thromboxane-2 (TXA-2)

Question 18

In general, COX-1 is constitutive and COX-2 is inducible but EXCEPTIONS include…

Answer 18

Expression of COX-2 in the kidney, synovial joints, CNS and female reproductive system.

Question 19

The renal adverse effects of NSAIDs are due to inhibition of…

Answer 19

Both COX-1 and COX-2

Question 20

List at least THREE renal adverse effects of NSAIDs?

Answer 20

Increased sodium retention, water retention following sodium retention, risk of hyperkalaemia, and changes in renal blood flow dynamics.

Question 21

List at least FOUR NSAIDs ranked from most strongly antiplatelet to most strongly prothrombotic.

Answer 21

Aspirin > Ketoprofen > Indometacin > Naproxen > Ibuprofen >Piroxicam > Diclofenac > Mefenamic acid > Celecoxib > Parecoxib > Etoricoxib

Question 22

Alcohol increases the hepatoxicity of paracetamol by altering its metabolism through…

Answer 22

Inducing minor pathway enzymes resulting in toxic metabolites and depleting glutathione, which is required to detoxify the toxic metabolites to nontoxic metabolites

Question 23

Hepatoxicity of paracetamol (acetaminophen) overdose can be treated with…

Answer 23

N-acetyl-cysteine helps to treat paracetamol toxicity by replenishing glutathione, which detoxifies the toxic metabolites of paracetamol to nontoxic metabolites

Question 24

The coxibs are markedly safer than non-selective NSAIDs for patients…

Answer 24

At risk of stomach ulcers

Question 25

List at least THREE adverse effects of COX-1 inhibition

Answer 25

Increased risk of nausea and vomiting, gastro-oesophageal reflux, stomach ulcers, bruising/bleeding, renal adverse effects contributing to hypertension and fluid retention. (Note that COX-2 inhibition also contributes to renal adverse effects).

Question 26

Name an NSAID available in a patch formulation suitable for lower back pain

Answer 26

Ketoprofen or diclofenac

Question 27

Name TWO NSAIDs available in topical gel or cream formulations

Answer 27

Piroxicam, diclofenac, ketoprofen

Question 28

What are the mechanisms of analgesic action of tramadol?

Answer 28

Tramadol is (1) a weak opioid analgesic with (2) additional norepinephrine and serotonin (5-HT) re-uptake inhibition

Question 29

What are the MOST LIKELY adverse effects of tramadol?

Answer 29

Constipation, nausea, vomiting

Question 30

Which relatively common adverse effect of tramadol is it typically MOST IMPORTANT to warn patients about?

Answer 30

Sedation/drowsiness - can result in accidents (e.g., if driving or operating machinery) or falls and fractures in the elderly. Sedation can be more severe if tramadol is combined with other CNS depressants (e.g., alcohol).

Question 31

Name TWO rare but SEVERE adverse effects of tramadol

Answer 31

Risk of dependence, respiratory depression at very high doses (can result in death on overdose or combination with other CNS depressants, e.g., alcohol)

Question 32

Combination of NSAIDs with which two classes of drugs greatly increases the risk of acute renal injury?

Answer 32

Combination of NSAIDs with (1) diuretics and (2) angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) greatly increases the risk of acute renal injury.

Question 33

Briefly describe the mechanism(s) of action of orphenadrine

Answer 33

Orphenadrine is a central muscle relaxant blocking muscarinic receptors in the basal ganglia in the brain. Additionally, it has H1 antihistamine, NMDA receptor antagonism, norepinephrine and dopamine re-uptake inhibitor and sodium channel blocker actions that may contribute to adjunct analgesic and muscle relaxant actions.

Question 34

List THREE common adverse effects of orphenadrine

Answer 34

Nausea and vomiting, flushing, dilated pupils, dry mouth

Question 35

List THREE adverse effects of orphenadrine seen only at higher doses

Answer 35

Tachycardia, ataxia, nystagmus, drowsiness, delirium, agitation, visual hallucinations

Question 36

Name an analgesic available in a combined formulation with orphenadrine

Answer 36

Paracetamol, mefenaminc acid. Note that paracetamol alone is usually insufficient for acute lower back pain but in combination with orphenadrine may be effective.

Question 37

Name a muscle relaxant used for acute (< 4 weeks) pain

Answer 37

Orphenadrine

Question 38

Briefly describe the mechanism(s) of action of diazepam

Answer 38

Allosteric modulator of GABA-A receptors increasing the frequency of opening of chloride channels and hence the potency of endogenous GABAergic neurotransmission
Suppresses brain reticular activating system: sedation, amnesia, loss of consciousness
Increased inhibitory neurotransmission also has anticonvulsant and muscle relaxant effect

Question 39

List THREE significant adverse effects of benzodiazepines

Answer 39

Drowsiness, impaired judgement, reduced motor skills, tolerance and high potential for dependence.

Question 40

Briefly describe the mechanism(s) of action of baclofen

Answer 40

GABA analogue that selectively activates GABA-B receptors in CNS
? Reduces tonic neural stimulation to muscles

Question 41

What is the risk associated with discontinuation of baclofen?

Answer 41

Abrupt cessation causes withdrawal syndrome:
- Potentially life-threatening withdrawal syndrome.
- Common effects are hyperthermia, pruritus, and increased spasticity.

Question 42

Name TWO adverse effects of baclofen

Answer 42

Sedation, weakness, and other CNS effects. Additionally, abrupt cessation causes a potentially life-threatening withdrawal syndrome.

Question 43

Name a gabapentinoid

Answer 43

Gabapentin, pregabalin

Question 44

Briefly describe the mechanism(s) of action of gabapentionoids

Answer 44

GABA analogues but act at voltage-gated calcium channels rather than GABA receptors.
? Reduces tonic neural stimulation to muscles.

Question 45

List TWO side effects of gabapentinoids

Answer 45

Somnolence, dizziness, ataxia (greater incidence if not titrated over days to weeks)

Question 46

Which antidepressant commonly used as an adjunct for chronic pain has LEAST risk of adverse effects?

Answer 46

While all antidepressants have a risk of adverse effects, duloxetine is a more selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor (SNRI) than the tricyclic antidepressants (e.g., amitriptyline), which have antihistamine, anticholinergic and alpha-1 antiadrenergic adverse effects.

Question 47

Which antidepressant commonly prescribed as an adjunct for chronic pain is MORE EFFECTIVE for lower back pain?

Answer 47

Duloxetine is usually more effective than tricyclic antidepressants (e.g., amitriptyline) for chronic lower back pain.

Question 48

List THREE major mechanisms of adverse effects of amitriptyline and at least ONE example of an adverse effect caused by each mechanism

Answer 48

Antihistamine: Sedation, weight gain
Anticholinergic: Blurred vision, dry mouth, urinary retention, constipation, agitation, tachycardia, heating (due to block of sweating)
Alpha-1 adrenoceptor blockade: Postural hypotension, tachycardia

Question 49

Briefly describe the mechanisms of action of topiramate

Answer 49

Inhibits excitatory neurotransmission:
- Blockade of AMPA subtype glutamate receptors
- Blockade of voltage-sensitive Na+ channels
May also potentiate inhibitory GABAergic neurotransmission
Together the above mechansims ? reduced tonic neural stimulation to muscles

Question 50

List THREE adverse effects of topiramate

Answer 50

Dizziness, fatigue, ataxia, confusion (although note that the adverse effects are usually mild)

Question 51

List the THREE major classes of drug used for muscle pain

Answer 51

Analgesics, muscle relaxants and adjuncts

Question 52

List the THREE major classes of muscle relaxants used for muscle pain and ONE example of a drug for each class

Answer 52

Central muscle relaxants (e.g., orphenadrine), benzodiazepines (e.g., diazepam), GABA derivatives including GABA-B agonists (e.g., baclofen) and gabapentinoids (e.g., gabapentin, pregabalin)

Question 53

List the TWO major classes of adjuncts used together with analgesics for subacute or chronic muscle pain and ONE example of a drug for each class

Answer 53

Anticonvulsants (e.g., topiramate or gabapentinoids such as gabapentin, pregabalin) and antidepressants (e.g., SNRIs such as duloxetine, or tricyclic antidepressants such as amitriptyline)