Lec 9- Analgesia II

Question 1

Definition of pain

Answer 1

• An unplesant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage
• BUT pain is very individual, so can be described as “What that patient says it is”

Question 2

Classification of pain

Answer 2

• Acute pain- usually has a diagnosable cause and an inherently protective function
• Chronic pain- doesn’t have a protective function. Longstanding (> 3 months); often an adaptation of autonomic nervous system leading to physical and psychological effects
  
  • Nociceptive- physical cause (a tumour, cut)
  • Neuropathic- Nerve damage, difficult to treat

Question 3

Describing pain (SOCRATES)

Answer 3

• Site
• Onset
• Character
• Radiation- is it in one place
• Associated symptoms- visual, hearing, tingling, nausea
• Timing (duration, course, pattern)
• Exacerbating and relieving factors
• Severity

Question 4

Pain intensity scales

Answer 4

Question 5

WHO analgesic ladder

Answer 5

Question 6

Prescribing analgesia

Answer 6

• Oral administration whenever possible- patches are available but v.expensive
• Should be given at regular intervals
• Prescribe according to pain intensity as evaluated by a scale of intensity of pain
• Dosing of pain medication should be adapted to the individual
• 40% GP visits are about pain- possibly up to 70%

Question 7

Step 1- Non-Opioid- Paracetamol

Answer 7

• Thought to act through inhibition of CNS prostaglandins
• Analgesic; no anti-inflammatory activity
• Adult dose: 1 gram q.d.s (unless malnourished/ liver probs)
• Often under-utalised
• Hepatotoxicity in overdose, but safer than NSAIDs and opioids for chronic use at advised dose
• Often appropriate as first line, including for OA
• Oral (P medicine up to quantity of 32 x 500mg) IV, rectal
• Can take in combination with all other analgesics

Question 8

Step 1- Non-opioid- NSAIDs

Answer 8

• Inhibition of enzyme cyclo-oxygenase => Inhibition of prostaglandins (selectivity of COX varies)
• Analgesic and Anti-inflammatory
• The full anti-inflammatory effect may take up to 3 weeks
• About 60% of patients will respond to anyone NSAID
• Over-used in the UK, esp in the elderly
• Side effects: GI- all systemic NSAIDs cause this, renal- AKI, cardiac- cause sodium and potassium retention
• Ever increasing evidence of increased risk of thrombotic events, i.e. MI and stroke
• Use for the shortest time at the lowest effective dose

Question 9

Opioid Analgesics

Answer 9

• Receptor types- Mu, Kappa, Delta
• Different opioid analgesics have different affinities for the receptors => different potencies and side effect profiles
• Pharmacogenetics possible cause of inter-individual response
• Agonists, partial agonist and mixed agonist/antagonists
• Use in combination with non-opioid and adjuvants
• Useful for actue and chronic pain
• Until recently, considered ineffective for neuropathic pain

Question 10

Opioid analgesics- problems

Answer 10

• Respiratory depression- Reverse with naloxone (Mu ++, delta +)
• Pupillary constriction- (Mu++, Kappa +)
• Cough suppressant
• Sedation- Mu
• Nausea and vomiting (Mu in CTZ)
• Constipation- Mu, Kappa, Delta
  
  • Regular stimulant and softening laxatives
  • Severe- methylnaltrexone bromide (s/c)
• Euphoria/Dysphoria (Mu, Kappa)
• Tolerance
• Addiction/ physical dependence

Question 11

Step 2- Weak Opioids

Answer 11

• Use in combination with non-opioid
• Many combination products on UK market
• Codeine (Mu receptor)
  
  • Pro-drug of morphine; 10% demethylated to form
  • Morphine; 8% of Caucasians are CYP2D6 poor metabolisers, so reduced analgesic effect
  • Also, consider CYP2D6 ultra-rapid metabolisers e.g. 29% of African/Ethiopian- increased risk of ADRs (also children)
  • Constipation; cough suppressant
• Dihydrocodeine (u Receptor)- Potency also 1/10^th that of morphine

Question 12

Weak Opioid- tramadol

Answer 12

• Action partially opioid and partially pre-synaptic re-uptake blockade of NA and 5-HT
• Potency 1/10^th of morphine
• Little effect in patients lacking iso-enzyme CYP2D6
• Interactions with drugs affecting CYP3A4 and CYP2D6
• Use with caution in patients with low seizure threshold

Question 13

Weak opioid- Tapentadol

Answer 13

• Agonist at u receptor AND inhibits re-uptake of NA
• No active metabolites
• Dose does not need to be decreased in hepatic or renal impairment
• BUT fiarly new to market, so little clinical experience with this drug

Question 14

Step 3- Strong Opioids- Morphine

Answer 14

• Oral opioid of choice in the UK
• Acts at u receptor (partial agonist)
• Comparator for potency (1.0)
• Metabolised to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)
• M6G is an active metabolite
• Both metabolites renally excreted
• The range of preparations (brand prescribe MR preps- differences between brand)
• Start with immediate release preparation; move onto MR preps with immediate release breakthrough pain

Question 15

Strong opioids- Diamorphine

Answer 15

• Potency 2.5
• Pro-drug of morphine
• Greater water solubility as the salt so parenteral alternative to morphine if need high doses
• Highly lipid soluble, so crosses BBB more rapidly than morphine => more rapid onset, but also offset => increased addiction potential

Question 16

Strong opioids- Fentanyl

Answer 16

• Acts on Mu receptor (100 x more potent than morphine)
• Metabolished to inactive metabolites by CYP3A4
• Transdermal patch useful as alternative to oral morphine (unable to tolerate morphine or unable to take oral medication)
• ​Transdermal inappropriate for severe uncontrolled pain where rapid dose titration needed
• Not advisable unless opioid requirement >30mg oral morphine a day
• Bran prescribe patches/PK considerations
• Transmucosal formulations

Question 17

Strong opioids- Alfentanil

Answer 17

• Rapid onset of action
• Short duration of action
• Alternative to diamorphine as s/c infusion
• Metabolised in liver to inactive compounds- used in patients with renal failure
• Commonly used in ITU situation

Question 18

Strong opioids- hydromorphone

Answer 18

• Acts at Mu receptor
• Potency 5-10 (~7.0)
• Metabolised to 3 glucoronide, which is renally excreted
• Alternative if intolerant to oral morphine
• Not used much in UK

Question 19

Strong Opioids- Oxycodone

Answer 19

• Acts at Mu and Kappa receptor
• Potency 2.0
• Half life doubles in both renal hepatic failure, not unlike other strong opioids
• Variety of formulations
• Not widely used in UK (morphine intolerant)

Question 20

Strong opioids- Methadone

Answer 20

• Acts at Mu and Delta receptors; plus it is an NMDA-receptor antagonist
• Used by specialists for difficult to control pain
• Long t^1/2
• Accumulates on chronic dosing
• Unaffected by renal or liver impairment

Question 21

Strong Opioid- Buprenorphine

Answer 21

• Partial agonist at Mu receptor (very high affinity; long t^1/2)
• Antagonist at Kappa receptor
• Virtually impossible to reverse with naloxone
• Oral => extensive metabolism, so buccal or transdermal
• Transdermal patch may be alternative to oral morphine at low-middle morphine dose range

Question 22

Adjuvants

Answer 22

• At any step of WHO analgesic ladder
• Often needed for neuropathic pain
• Tricyclic anti-depressants
• Anti-convulsants
• BZ
• Lidocaine- As a patch
• Corticosteroids
• Ketamine, Biphosphonates, membrane stablisers

Question 23

Neuropathic pain

Answer 23

• Does not follow the WHO analgesic ladder
• NICE recommend 4 drugs first-line:
  
  • Gabapentin- 2019 will be a CD
  • Pregabalin- 2019 will be a CD
  • Amitriptyline
  • Duloxetine
• Check effective before continually prescribing- titration individualised
• Some benefit within days but can take 4 weeks before the maximal effect