Introduction to the pharmacology of analgesic agents Flashcards
Analgesia requirements
Appropriate treatment of dental pain
Knowledge of patients concurrent analgesic medications
for chronic pain
Recognition of adverse effects and avoidance of potential
interactions.
Pain definition
An unpleasant sensory and emotional experience which
we primarily associate with tissue damage or describe in
terms of tissue damage or both (IASP definition)
Inadequate pain relief
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
How many people in the UK suffer from persistent pain?
About 40%, or as many as 28 million people
Pain normal –>
injury pain path
protective –> acute or prolonged (interchangeable)
acute –> reflexes
prolonged –> inflammation and repair
Congenital insensitivity to pain
SCN9A gene mutation in humans:
-Nav1.7 voltage-gated sodium channel mutations in the asubunit
cause loss of function
Sources of pain
Injury
Disease
Sensory pathways
Transduction
Perception - somatosensory cortex
Transmission - thalamus, spinal cord, sensory fibres (touch, pain)
Perception/ learning - limbic (amygdala)
Pain modulation
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
Chronic pain path
Abnormal –> non-protective –> chronic (pain as disease)
Therapeutic goal of prolonged or chronic pain
Return sensitivity to normal
thresholds, without loss of
protective function
Dental pain
Infection - Acute inflammation
Exposed nerve endings: neurogenic pain
Swelling in confined space: pressure effects
Fear and anxiety
Treatment of pain
Reduce Tissue damage: -non steroidal anti-inflammatory drugs (NSAIDS) -steroids -cooling Nerve block: LAs -spinal Cord: opioids CNS: -opioids -psychological factors
WHO: cancer pain relief
Believe patient History of symptoms Assessment of severity Physical examination Appropriate pain management
WHO Analgesic ladder
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
Analgesic ladder assumptions
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
Placebo effect
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
WHO analgesic ladder: paracetamol
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
WHO analgesic ladder: paracetamol - adverse effects
Uncommon
Hepatotoxicity if overdose. Early treatment with
N-acetyl-cysteine
Not absolutely contraindicated in liver disease
WHO Analgesic Ladder: NSAIDs
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
WHO Analgesic Ladder: NSAIDs - GIT
Occult GI blood loss from minor breaches in mucosa (loss of PGE). Peptic ulceration.
General GI upset, indigestion
WHO Analgesic Ladder: NSAIDs - Renal function
Reduction in intrarenal blood flow can cause renal failure
WHO Analgesic Ladder: NSAIDs - platelets
COX inhibition, bleeding tendency
WHO Analgesic Ladder: NSAIDs - CV
As a result of altered renal function,
fluid retention can precipitate heart failure
WHO Analgesic Ladder: NSAIDs - respiratory
Some ‘aspirin sensitive’ asthmatics
WHO Analgesic Ladder: NSAIDs - examples
Ibuprofen, Naproxen, Diclofenac
Newer COX2 Inhibitors: Parecoxib Celecoxib
COX 2: Less bleeding as GI tract and Platelets have
mainly COX1
Not less nephrotoxic
COX2 and CV disease
Absence of antiplatelet effects
Slightly pro thrombotic
> risk MI and Stroke
–> contraindicated
NSAIDs and elective surgery
Need to stop at least 5 days before elective surgery
Bleeding at operation: platelet transfusion
Consider platelets if emergency surgery
Weak opioids - moderate - severe pain
Codeine/ Di-hydrocodeine
- both are metabolised to morphine. Metabolism
varies. Some people have minimal enzyme and hence less effective. - weak opioid effects
Weak opioids - moderate - severe pain: CV
Reduced sympathetic outflow,
increased vagal tone. Bradycardia, hypotension,
excitation
Weak opioids - moderate - severe pain: respiratory
Inhibit cough reflex, respiratory depression
Weak opioids - moderate - severe pain: GIT
< gastric motility. Constipation, nausea
and vomiting.
CNS opioid effects
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.
Reversal of opioid effects
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
Opioid dependency
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
Newer oral opioids
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
Tramadol adverse effects
> 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
Weak opioid/ paracetamol combinations
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
Group cautions prescribing opioids
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
WHO analgesic ladder - severe pain
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
Post op analgesia
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
Morphine px controlled post op analgesia
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
Routes of opioids administration
Oral i.v. s.c. and i.m. Rectal Intrathecal Epidural Buccal Trans dermal
Severe pain: chronic pain
Oral morphine syrup or tablets Morphine s.c. infusion Diamorphine s.c. infusion Fentanyl transdermal patch lasts 5 days Buprenorphine patch
Gabapentin and pregabalin (type of co-analgesic)
Effective for chronic neurogenic pain
< central transmission and pain projection
Adverse effect: sedation, dizziness, nausea,
occasionally hypotension
Antidepressant drugs (type of co-analgesic)
Amitryptiline
Duloxetine & Citalopram
Have useful adjuvant effects in neurogenic pain.
Also some antidepressant effects can be useful.
Adverse effects GI and CVS
Co-analgesics
Other drugs, nerve blocks, surgery, radiotherapy, complementary therapies, addressing psychosocial issues
Pain management
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
