Analgesia Flashcards
What is the definition of pain?
An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.
Describe (P)RAT.
- Prevent - it is important to prepare a patient for any pain you will inflict as their doctor.
- Recognise
- Assess
- Treat
Which questions must you ask yourself before you inflict pain on a patient?
- Do I need to do this?
- Can I do it skillfully and quickly?
- Can I minimise the pain?
- Pre-emptive analgesia (anticipate pain).
List non-pharmacological techniques of pain management.
- Treat the underlying cause (eg. reduce / immobilise the fracture).
- RICE (cold pack for first 72 hours post minor MSK injury).
- Explanation / education / reassurance.
- Change of focus away from pain (distraction).
- TENS
- Hypnosis
- Acupuncture
What is step 1 on the reverse WHO ladder?
- Mild pain
- Continue simple analgesics
What is step 2 on the reverse WHO ladder?
- Moderate pain
- Use mild opioid eg. codeine, tramadol.
- Continue simple analgesics.
What is step 3 on the reverse WHO ladder?
- Severe pain
- Use strong opioid eg. morphine.
- Also continue to use simple analgesics.
- Start at this level for acute nociceptive pain. Go down the ladder as the patient gets better and the pain decreases.
Which questions must you ask yourself before pescribing?
- Which drug am I going to give this patient for this problem?
- Which route am I going to give it by?
- What dose? (What weight is the patient, is there a reason to reduce the dose?)
- How often? (Are the kidneys working? Increase length of dose if you are worried about renal function) Regularly or as required?
- Any adjuvant prescribing required?
- When prescribing opioids, remember a laxative and possibly an antiemetic.
What are the possible routes of administration for pain medication?
- Topical
- Oral
- IM injection
- IV infusion
- Lolipops
- Directly into the CNS (dose is much smaller)
- Transcutaneous
- Per rectum
What are the properties of paracetamol?
- Reduces pain (analgesic agent) and has anti-pyretic ability.
- Can be administered orally or per rectum.
- Effective within 40-60 minutes.
- Variable bioavailability.
What are the properties of Falgan?
- IV paracetamol
- Onset within 5 minutes, peak effect at 40-60 minutes.
- Lasts 4-6 hours.
Describe how paracetamol works.
- Paracetamol acts centrally in the brain, as opposed to the actual site of tissue damage.
- It acts on the peroxidase site, then have an effect on the cox enzymes.
- The end result is that is diminishes the amount of prostaglandins produced.
- It stimulates serotinergic pathway involved in descending inhibition.
- Pain is modulated in the dorsal horn. There is a descending inhibitory pathway which comes from the periaqueductal gray matter through the medulla and acts on the dorsal horn.
- It stimulates this inhibitory descending pathway.
- Third mechanism of action is the anti-pyretic effect.
What are the positives of using paracetamol?
- SAFE AND EFFECTIVE
- Cheap
- Number needed to treat (compared to placebo) ~4 to achieve a >50% reduction in moderate pain over 4-6 hours.
- Safe in theraputic dosage.
- Synergistic effect with NSAIDs and opioids (allows less use of these).
- Antipyretic action but poor anti-inflamatory action.
Describe the pharmacokinetics of paracetamol.
- Absorbed from the small bowel.
- High, but variable bioavailablilty.
- Metabolised in the liver.
Describe the effects of paracetamol toxicity.
- Foremost cause of acute hepatic failure in the UK.
- Symptoms:
- <8 hours of nausea / vomiting
- 12-36 hours - usually no symptoms
- 24-72 hours - hepatic failure
What is the treatment for acute hepatic failure secondary to paracetamol toxicity?
N-acetyl cysteine
Describe the properties of NSAIDs.
- Anti-inflammatory
- Analgesic
- Anti-pyretic
- All of these actions are related to the primary action of these drugs:
- Inhibit prostaglandin biosynthesis by direct action on cyclo-oxygenase enzymes.
- Paracetamol has an indirect mechanism of action, NSAIDs are DIRECT.
What is the mechanism of action of NSAIDs?
- All inhibit cyclo-oxygenase (COX) but do so by two main mechanisms:
- (1) - an irreversible, time-dependent inhibition of the enzyme (aspirin).
- (2) - A rapid, reversible competitive inhibition of the enzyme (the rest).
- Eg. ibuprofen, naproxen.
- Binds reversibly to the enzyme.
- Competes with natural substrate, arachidonic acid.
- Clinically, aspirin is most commonly used as an anti-platelet drug.
What is Reye’s syndrome?
- A rare, but life-threatening disorder of children or young adults.
- Children under 16 should not take products containing aspirin.
- Usually occurs following a viral illness (+ingestion of aspirin).
- Persistent uncontrolled vomiting and altered consciousness.
- Still GCS15 but working really hard to orientate themselves.
- Derangement of liver enzymes.
Describe prostaglandins.
- Inflammation is always accompanied by the release of prostaglandins.
- Predominantly PGE2 but also PG12.
- PGD2 from mast cells.
- PGE2, PG12 and PGD2 act as potent vasodilators.
- Also synergise with other inflammatory mediators (eg. histamine and bradykinin).
- Potentiate histamine and bradykinin actions on postcapillary venule permeability and pain sensory nerves.
Describe COX-1
- Constitutive
- Important in maintaining GIT integrity.
- Important in maintaining the gut mucosa. If you inhibit them you are more likely to cause GI bleed and peptic ulceration.
Describe COX-2
- Inducible
- Involved in inflammatory response.
- Implicated in cancer development.
- COX2 isn’t always around but it comes forqward in cancer and is heavily involved in pain.
- There is an increase in thrombotic action - people having strokes and MIs because they were on these drugs.
- So, it is mostly COX1 inhibitors which are prescribed.
Describe the anti-pyretic effect of NSAIDs.
- Body temperature is regulated by the hypothalamus.
- Fever occurs when the hypothalamic thermostat ‘set-point’ is raised.
- Bacterial endotoxins cause release of factors (eg. interleukin 1) from macrophages.
- Interleukin 1 causes generation of prostaglandins in the hypothalamus (PGEs).
- Prostaglandins increase the thermostat ‘set-point’.
- Therefore, NSAIDs act by preventing the formation of prostaglanding and prevent the rise in temperature.
- No effect on normal body temperature.
What are the properties of non-selective NSAIDs?
Give examples.
-
Propionic acids
- Eg. ibuprofen, naproxen
- Not prodrugs
- Well absorbed
- Last for 4-6 hours
-
Fenamates
- Eg. mefenamic acid
- If a patient is at risk of a GI bleed, you should also prescribe a proton pump inhibitor when you prescribe a COX1 inhibitor.
What are the clinically important side effects of NSAIDs?
- GI complications
- Chronic kidney disease
- NSAID related hypersensitivity (can provoke wheeze in certain patients).
- Cardiovascular disease (reduced efficacy of ACEI) - it can minimise the decrease in BP resulting from the ACE-inhibitor - it minimises the effect of the ACEI.
- Thrombotic sequelae
- Bone healing - good for bone pain but have a negative impact on bone healing.
What are the interactions of NSAIDs which cause renal impairment?
ACE inhibitor + NSAIDs + diuretic = renal impairment.
Give examples of strong opioids.
- Morphone
- Oxycodone
- Diamorphine
- Fentanyl
- Pethidine
- Remifentanil
- Methadone
Give examples of weak opioids.
- Codeine
- Dihydrocodeine
- Loperamide
What are the antagonists used or opioids?
- Naloxone
- Naltrexone
What is loperamide?
- An opioid which is not an analgesic.
- Works on the myenteric plexus in the gut.
- Trade name = immodium.
What are the sites of action of opioids?
- MU opioid receptors (MOP)
- Kappa (KOP)
- Delta (DOP)
- Nociception (NOP)
What is the most powerful analgesic site?
MU opioid receptor
Describe the effects of opioids at a cellular level.
- When an opioid attaches to a receptor it has 2 effects:
- It opens potassium channels - high concentration inside cell, low concentration outside the cell, so potassium goes out.
- Closes calcium channel so calcium doesn’t enter the cell.
- Minimised the conversion of ATP to cAMP.
- Ultimate effect is reduced neurotransmitter release. So, it dampens the nervous system.
What is the effect of opioids on the cardiovascular system?
- Bradycardia
- Direct action on the SA node
- Direct action on the sympathetic drive
- Decreased sympathetic drive
- Morphine releases histamine
- Causes peripheral vasodilation
- Overall effect is that patient experiences drop in blood pressure.
What are the actions of opioids on the central nervous system?
- Analgesia
- Sedation - might be a good thing, but a problem in prescribing opioids for chronic pain.
- Euphoria - post major trauma this is a good thing but it makes the drug one of misuse and dependence.
- Acts on CN3 and causes pinpoint pupils.
What are the actions of opioids on the respiratory system?
- Depresses respiration
- Decrease respiratory rate
- Decrease tidal volume
- This decreases minute volume (blood gas = increased pCo2).
- The effector is the respiratory system but actually the effect of the opioid is on the CNS (it acts on the MOP receptors in the brainstem).
- Anti-tussive action (stops patient coughing) - can be very useful in palliative care (tumour pressing on the lung, or endotracheal tube toleration).
- Morphine releases histamine and can cause wheeze (bronchoconstriction) in vulnerable patients.
What are the actions of opioids on the GI tract?
- Delayed motility in the gut.
- Direct action on the chemoreceptor trigger zone.
- Action on the vestibular apparatus.
-
All of these are likely to cause nausea.
- If a patient is on opioids for a prolonged period, they develop tolerance to the nausea, but when starting an opioid you MUST prescribe an antiemetic.
- Constipation
- Continuous laxative
What are the other, non-specific effects of opioids?
- Urticaria
- Itch
- Urinary retention
- Immunosuppression - thought to be via natural killer cells.
- Effect on pituitary and hypothalamus hormones (these are the origins of the naturally occuring endogenous opioids)
- Decreased prolactin
- Increased ADH
- Changes to these hormones is likely to be a feedback mechanism.
Describe the effect of pharmacogenetics on codeine.
- Codeine is a prodrug - it has no effect until it is metabolised.
- In slow metabolisers you can give them codeine and it is useless. It has no analgesic effect.
- In faster metabolisers, the same dose would equal an overdose.
- Contraindicated in children because of the pharmacogenetics.
Where are the majority of drugs metabolised?
The liver
The majority of drugs are metabolised to the liver.
Give an example of an exception to this.
- Remifentanil
- Metabolised by plasma esterases
- So, it has a very short action
- Usually given by infusion
- Usually given as an anaesthetic
Describe how morphine is metabolised?
- Metabolised to the liver, but is metabolised to active metabolites which are excreted by the kidney.
- So, if you give morphine to a patient with chronic kidney disease, its effect will be prolonged.
What are the markers of opioid toxicity?
- If the patient has:
- Drowsiness
- Pinpoint pupils
- Decreased respiratory rate
- Think about whether the patient is being overdosed with opioids.
Describe the effect of an opioid antagonist.
Give an example.
- An antagonist is a drug with a high affinity for the receptor but no intrinsic activity.
- Naloxone will reverse effects of an opioid overdose.
- Naltrexone is an opioid antagonist but is used to maintain people who have got clean from opioids.
- Shorter acting than opioids
- May have to repeat the dose or start a naloxone infusion.
What is methadone?
A long-acting opioid
Define tolerance.
A physiological state characterised by a decrease in the effects of a drug with chronic administration.
You need to give increasing dose to get the same effect.
Define dependence.
The drug induces a rewarding experience. Drug takin becomes compulsive.
Define withdrawl.
A group of symptoms which occur on cessation of a psychoactive substance that has been taken over a prolonged period. There may be physiological disturbance. Withdrawl indicated dependence.
What are the 2 mainstays of treatment for neuropathic pain?
- Tricyclic antidepressants
- Gabapentin / pregabalin
Describe the properties of tricyclic antiepressants.
- Primary mechanism of action is pe-synaptic inhibition of NA and 5-HT reuptake.
- Enhances descending inhibition (‘damping’) of pain in the dorsal horn.
- Analgesic effect is separate from anti-depressant effect.
- Analgesic effects in a few days to a week.
- Anti-depressant effects take 2-4 weeks.
- Small dose (25-75mg) at night.
- Side effects (which often limit use):
- Sedation
- Dry mouth
- Constipation
- Urinary retention
- Contraindicated post MI
Describe the properties of gabapentin / pregabalin.
- Primary mechanism of action is via voltage gated calcium channels.
- Thought as a result to disrupt NMDA receptor pain.
- Significant euphoric effects.
- Excreted unchanged in urine so take note if patient has chronic kidney disease.
- Minimal side effects other than drowsiness.
