Introduction to the pharmacology of analgesic agents

Question 1

Analgesia requirements

Answer 1

Appropriate treatment of dental pain
Knowledge of patients concurrent analgesic medications
for chronic pain
Recognition of adverse effects and avoidance of potential
interactions.

Question 2

Pain definition

Answer 2

An unpleasant sensory and emotional experience which
we primarily associate with tissue damage or describe in
terms of tissue damage or both (IASP definition)

Question 3

Inadequate pain relief

Answer 3

Inadequate pain relief is a global concern for patients and
practitioners. Pain is not always cured and requires
continuous medical management, the same as any other
disease process

Question 4

How many people in the UK suffer from persistent pain?

Answer 4

About 40%, or as many as 28 million people

Question 5

Pain normal –>

injury pain path

Answer 5

protective –> acute or prolonged (interchangeable)
acute –> reflexes
prolonged –> inflammation and repair

Question 6

Congenital insensitivity to pain

Answer 6

SCN9A gene mutation in humans:
-Nav1.7 voltage-gated sodium channel mutations in the asubunit
cause loss of function

Question 7

Sources of pain

Answer 7

Injury

Disease

Question 8

Sensory pathways

Answer 8

Transduction
Perception - somatosensory cortex
Transmission - thalamus, spinal cord, sensory fibres (touch, pain)
Perception/ learning - limbic (amygdala)

Question 9

Pain modulation

Answer 9

Emotion and attention profoundly modulate nociception.
The amount of pain experienced does not necessarily relate to the severity of tissue damage
Anxiety increases pain transmission
Complex cultural and contextual influences

Question 10

Chronic pain path

Answer 10

Abnormal –> non-protective –> chronic (pain as disease)

Question 11

Therapeutic goal of prolonged or chronic pain

Answer 11

Return sensitivity to normal
thresholds, without loss of
protective function

Question 12

Dental pain

Answer 12

Infection - Acute inflammation
Exposed nerve endings: neurogenic pain
Swelling in confined space: pressure effects
Fear and anxiety

Question 13

Treatment of pain

Answer 13

Reduce Tissue damage:
-non steroidal anti-inflammatory drugs (NSAIDS)
-steroids
-cooling
Nerve block: LAs
-spinal Cord: opioids
CNS:
-opioids
-psychological factors

Question 14

WHO: cancer pain relief

Answer 14

Believe patient
History of symptoms
Assessment of severity
Physical examination
Appropriate pain management

Question 15

WHO Analgesic ladder

Answer 15

Step 1: mild to moderate pain
-non-opioids + adjuvant analgesics
Step 2: moderate to severe pain
-weak opioids + non-opioids + adjuvant analgesics
Step 3: secere pain
-strong opioids + on-opioids + adjuvant analgesics

Question 16

Analgesic ladder assumptions

Answer 16

Synergism
Overall philosophy assessing severity, starting at
lowest level and > if necessary
Joint Royal Colleges Report (1988) quality of analgesia in hospital practice is inadequate

Question 17

Placebo effect

Answer 17

Placebo is anything administered which is
pharmacologically and physiologically inert
Placebo not ineffective therapeutically. Can
have a measurable effect
Reassurance and confidence in one’s therapy may also have effect

Question 18

WHO analgesic ladder: paracetamol

Answer 18

Mechanism of action unknown – Inhibitor of the
synthesis of prostaglandins.
Analgesic, antipyretic, not much anti-inflammatory
effect
Oral, soluble potions, intravenous, rectal
1g 4- 6 hourly adult dose 4g in 24h

Question 19

WHO analgesic ladder: paracetamol - adverse effects

Answer 19

Uncommon
Hepatotoxicity if overdose. Early treatment with
N-acetyl-cysteine
Not absolutely contraindicated in liver disease

Question 20

WHO Analgesic Ladder: NSAIDs

Answer 20

Aspirin, Ibuprofen, Naproxen, Indomethacin…
Irreversible inhibitor of cyclo oxygenase (COX1 and/or
COX2) enzyme
COX generates inflammatory mediators: prostaglandins
and thromboxanes
COX widely distributed, different isotypes
COX inhibitors are effective at reducing acute
inflammation
Adverse effects due to extension of therapeutic effects

Question 21

WHO Analgesic Ladder: NSAIDs - GIT

Answer 21

Occult GI blood loss from minor breaches in mucosa (loss of PGE). Peptic ulceration.
General GI upset, indigestion

Question 22

WHO Analgesic Ladder: NSAIDs - Renal function

Answer 22

Reduction in intrarenal blood flow can cause renal failure

Question 23

WHO Analgesic Ladder: NSAIDs - platelets

Answer 23

COX inhibition, bleeding tendency

Question 24

WHO Analgesic Ladder: NSAIDs - CV

Answer 24

As a result of altered renal function,

fluid retention can precipitate heart failure

Question 25

WHO Analgesic Ladder: NSAIDs - respiratory

Answer 25

Some ‘aspirin sensitive’ asthmatics

Question 26

WHO Analgesic Ladder: NSAIDs - examples

Answer 26

Ibuprofen, Naproxen, Diclofenac Newer COX2 Inhibitors: Parecoxib Celecoxib COX 2: Less bleeding as GI tract and Platelets have mainly COX1 Not less nephrotoxic

Question 27

COX2 and CV disease

Answer 27

Absence of antiplatelet effects Slightly pro thrombotic > risk MI and Stroke --> contraindicated

Question 28

NSAIDs and elective surgery

Answer 28

Need to stop at least 5 days before elective surgery Bleeding at operation: platelet transfusion Consider platelets if emergency surgery

Question 29

Weak opioids - moderate - severe pain

Answer 29

Codeine/ Di-hydrocodeine - both are metabolised to morphine. Metabolism varies. Some people have minimal enzyme and hence less effective. - weak opioid effects

Question 30

Weak opioids - moderate - severe pain: CV

Answer 30

Reduced sympathetic outflow, increased vagal tone. Bradycardia, hypotension, excitation

Question 31

Weak opioids - moderate - severe pain: respiratory

Answer 31

Inhibit cough reflex, respiratory depression

Question 32

Weak opioids - moderate - severe pain: GIT

Answer 32

< gastric motility. Constipation, nausea | and vomiting.

Question 33

CNS opioid effects

Answer 33

Sedation, euphoria, (dysphoria), excitation ANALGESIA Spinal Cord: < pain fiber transmission kappa opioid receptors Brainstem: < pain projection to higher centers. Mu opioid receptors Respiratory depression, reduced brainstem response to hypoxia and hypercarbia.

Question 34

Reversal of opioid effects

Answer 34

Naloxone 400 mcg i.v. dramatic reversal of mu receptor opioid effects. Far less effective on newer synthetic opioid like substances as their effects in the CNS are less well defined

Question 35

Opioid dependency

Answer 35

Chronic opioid use: reduced effect as CNS becomes more tolerant. Dose increase. Acute withdrawal: Hypertension, tachycardia, tachypnoea, diarrhoea, sweating, anxiety, hallucinations. Any chronic opioid medication will precipitate some withdrawal reaction if stopped suddenly

Question 36

Newer oral opioids

Answer 36

Tramadol and Nefopam As effective as codeine, less variability, much less constipation hence very frequently prescribed. “Oramorph”lower dose oral morphine. Usual opioid effects: sedation, dizziness, nausea Occasionally flushing / sweating with tramadol

Question 37

Tramadol adverse effects

Answer 37

``` > number of fatalities from overdose causing respiratory depression. Dependency develops with long term use which is difficult to withdraw. New legislation: Controlled drug (class 3). Limit to maximum prescription. Must be signed for ```

Question 38

Weak opioid/ paracetamol combinations

Answer 38

Co-codamol, Co proxamol, various Now less popular than either nefopam or tramadol. Need to include the paracetamol in the total 24 h maximum of 4g Check BNF if an unfamiliar oral analgesic

Question 39

Group cautions prescribing opioids

Answer 39

Dependent on hepatic metabolism and renal excretion of metabolites. Some active metabolites Prolonged effect in liver or renal impairment Respiratory disease, sleep apnoea, increased sensitivity Aim for minimum duration of prescription

Question 40

WHO analgesic ladder - severe pain

Answer 40

``` Morphine; oral, s.c., i.v. Diamorphine s.c., i.v. Fentanyl patch (transdemal) Oral dose is approx 3x the i.v. dose for the same efficacy ```

Question 41

Post op analgesia

Answer 41

If required i.v. in recovery 2mg increments every 3 minutes until comfortable (10 to 20mg) in a recovery setting. Must be given by trained staff Ward care: Morphine 10mg s.c. 3 hourly usually coprescribed antiemetic; Ondansetron or cycizine

Question 42

Morphine px controlled post op analgesia

Answer 42

Syringe driver intermittent i.v. bolus delivery initiated by patient (push button) 1mg minimum frequency every FIVE minutes Multiple studies show: approximately 1/3 dose compared to nurse administered s.c. morphine

Question 43

Routes of opioids administration

Answer 43

``` Oral i.v. s.c. and i.m. Rectal Intrathecal Epidural Buccal Trans dermal ```

Question 44

Severe pain: chronic pain

Answer 44

``` Oral morphine syrup or tablets Morphine s.c. infusion Diamorphine s.c. infusion Fentanyl transdermal patch lasts 5 days Buprenorphine patch ```

Question 45

Gabapentin and pregabalin (type of co-analgesic)

Answer 45

Effective for chronic neurogenic pain < central transmission and pain projection Adverse effect: sedation, dizziness, nausea, occasionally hypotension

Question 46

Antidepressant drugs (type of co-analgesic)

Answer 46

Amitryptiline Duloxetine & Citalopram Have useful adjuvant effects in neurogenic pain. Also some antidepressant effects can be useful. Adverse effects GI and CVS

Question 47

Co-analgesics

Answer 47

Other drugs, nerve blocks, surgery, radiotherapy, complementary therapies, addressing psychosocial issues

Question 48

Pain management

Answer 48

Assessment of severity in context of daily living and functioning. Acute pain; large variation in requirements complex. The amount of analgesia required is “enough to stop the pain”. That is the correct dose. Synergism different drug actions, psychological factors