Clinical Use of Analgesics: Opioids and Other Medicines

Question 1

What is the mechanism of action of opioids?

Answer 1

Spinal level:

• Inhibits transmission of nociceptive signals through dorsal horn and spinal reflexes
• Inhibiting adenyl cyclase and thus decreasing cAMP
• Closure of VGCCs (less Glu release)
• Opening of K+ channels (cell hyperpolarisation)

Supraspinal:
- Inhibits descending signals to brainstem and spinal cord

Question 2

Which opioids are used for moderate and severe pain respectively?

Answer 2

Moderate pain:

• Codeine
• Dihydrocodeine
• Dextropropoxyphene

Severe pain:

• Morphine
• Diamorphine
• Oxycodone
• Fentanyl
• Tramadol

Question 3

When are opioids used for severe pain?

Answer 3

• Acute pain
• Persistent non-cancer pain
• Palliative care
• No ceiling effect; restricted by side effects

Question 4

What are the common side effects of opioids?

Answer 4

• Nausea & vomiting (40% of patients will experience)
• Constipation (reduced GI motility)
• Sedation
• Respiratory depression (bronchoconstriction as less sensitvity to pCO2 in respiratory centre)
• Hypotension
• Urinary retention

Question 5

What are the less common side effects of opioids?

Answer 5

• Narcotic bowel syndrome
• Immunosuppression
• Endocrine dysfunction
• Addiction

Question 6

How is opioid-induced constipation treated?

Answer 6

Non-pharmacological:

• Diet (high fibre)
• Fluids

Laxatives:
- Stimulant laxative (Senna) in combination with stool softener (Lactulose)

Peripherally restricted opioid antagonist:

• Methylnaltrexone (SC administration)
• Naloxone PR (in Targinact)

Question 7

How is oral morphine treatment initiated for pain?

Answer 7

• Pain assessment inc. current analgesia
• Determine opioid requirement: use short-acting preparation regularly, plus PRN dosing
• Calculate 24 hour requirements
• Convert to MR formulation e.g. MST, Zomorph
• 1/10 to 1/6 of total daily dose prescribed every 4 hours for breakthrough pain

Question 8

What is the procedure to change a patient onto an alternative opioid?

Answer 8

• Determine 24 hr requirement
• Use conversion factor for alternative opiate to determine new 24 hr requirement
• Convert to appropriate dosing regimen

Question 9

What is PCA and what opioids are involved?

Answer 9

• Patient can dose themselves up if analgesia required (bolus dosing)
• Morphine is drug of choice
• Tramadol, oxycodone or fentanyl used if morphine allergy

Question 10

What are the advantages of PCA?

Answer 10

• Rapid analgesia once pain at steady state (Css)
• Ready prepared
• Patient satisfaction
• No dose delay
• Patient acceptability
• No peaks or troughs

Question 11

What are the disadvantages of PCA?

Answer 11

• Expensive
• Requires IV access
• Training
• Monitoring

Question 12

When are epidurals used and what is entailed? Which drugs are used?

Answer 12

• Alternative to PCA esp. in maternity, lower limb, spinal or abdominal surgery
• Mixture of LA and opioid (synergistic action)
• Fentanyl + bupivacaine (or levobupivacaine)

Question 13

What are the adverse effects associated with epidural use?

Why is respiratory depression not a concern?

Answer 13

• Hypotension
• ‘Wrong route’
• Infection

+ Respiratory depression uncommon due to lipophilicity of fentanyl

Question 14

What are syringe drivers and the indications for its use?

Answer 14

• Continuous SC infusion

Indications:

• Nil by mouth e.g. N&V, dysphagia
• Bowel obstruction
• Patient does not wish to take regular medication by mouth

Question 15

What is the drug of choice for syringe drivers and why?

Answer 15

• Diamorphine

- Excellent aqueous solubility

Question 16

What other drugs are mixed in with diamorphine for syringe drivers and the indications?

Answer 16

• Haloperidol, cyclizine (N&V)
• Levomepromazine, midazolam (restlessness & confusion)
• Midazolam (seizures)
• Hyoscine N-butylbromide (excessive respiratory secretions)

Question 17

What is monitored during opioid therapy?

Answer 17

• Pulse
• BP
• RR
• Pain
• Oxygen saturation
• Sedation score
• Opioid usage
• Opioid side effects

Question 18

What is naloxone and how is it given?

Answer 18

• Opioid antagonist
• Higher affinity of opioid receptor than agonist (used in overdose etc)
• Short T1/2 when given IV (thus repeated doses may be necessary)
• May induce pain (knocking off opioid agonists)
• Titrate gradually until effect achieved

Question 19

What is tramadol and how does it work?

Answer 19

• μ-opioid receptor agonist (30% of analgesic affect; metabolised into more potent opioid agonist, O-Desmethyltramadol)
• This is formed from CYP2D6 metabolism like morphine from codeine; ceiling-effect in those lacking this enzyme
• Inhibits NA reuptake and releases 5-HT (inhibits that reuptake too?)
• More tolerable opioid side effect profile (e.g. less incidence of constipation)
• Potentially more pronounced N&V though

Question 20

Which tricyclic antidepressants are used for neuropathic pain and how do they work?

Answer 20

• Amitriptyline, nortriptyline

- Inhibits neuronal reuptake of NA and 5-HT

Question 21

How are tricyclic antidepressants implemented dosage-wise and why?

Answer 21

• Use limited by adverse effects

- Adverse effects minimised by starting with low dose and small incremental changes

Question 22

How are antiepileptic drugs effective for neuropathic pain? Name some.

Answer 22

• They block VGSCs (stabilise the inactive state) in peripheral neurones
• BUT high incidence of adverse effects thus limited license for neuropathic pain
  E.g. carbamazepine, phenytoin, sodium valproate

Question 23

How are anticonvulsants effective for neuropathic pain? Name two.

Answer 23

• Prevent VGCC activation (as well as NMDA interaction/enhancing descending noradrenergic pain control)
• No effect on VGSCs
• Fewer adverse effects and drug interactions than epileptics like carbamazepine
• Licensed for neuropathic pain

Question 24

How is capsaicin used for analgesia?

Answer 24

• TRPV1 receptor agonist
• Licensed for post-herpetic neuralgia (PHN)
• Counselling on application required (use EMLA)

Question 25

What are the principles of the WHO analgesic ladder?

Answer 25

• By the clock
• By the mouth
• By the ladder
• Individual dose titration
• Use adjuvant drugs
• Attention to detail