Week 9: Pain Management Flashcards
Briefly list the components of the ‘pain pathway’
i. Painful stimuli carried by afferent ‘C’ fibres
ii. Following trauma/injury surrounding tissue and neurons synthesise PGs - PGE2 in particular
iii. Other autacoids released - notably Bradykinin
iv. PGE2 binds with ‘C’ fibre neuronal EP1 GPCR receptor
v. GPCR receptor: Increased neuronal sensitivity to Bradykinin, Inhibition of K+ channels, Increased Na+ channels sensitivity
vi. Increased sustained nociceptive signalling peripherally result in ↑ cytokine levels in dorsal horn cell body
vii. This causes Inc COX-2 synthesis and Inc PGE2 synthesis
viii. PGE2 then acts via local GPCR EP2 receptor (Gs Type)
ix. This increase sensitivity + discharge rate of secondary interneurones
x. One aspect is removal of glycinergic inhibition
What are the 3 principle classes of drugs used for pain relief? List some commonly used drugs in each class.
NSAIDs eg aspirin ibuprofen
Paracetamol
Opiates e.g. morphine, codeine
What are the main uses in clinical medicine of the 3 classes of agents
Pain relief
NSAIDs for soft tissue injury & musculoskeletal pain of mild to moderate intensity with anti-inflammatory benefit – useful in rheumatoid arthritis. Have fewer ADRs than opiates.
Paracetamol where NSAIDs are contraindicated e.g. GI complaints, where prolongation of bleeding is undesirable, children (risk of Reyes syndrome
with NSAIDs) and antipyretic
Opiates for moderate to severe pain, particularly of viscera: severe pain in palliative care, part of acute coronary syndrome (ACS) management, pancreatitis
Compound analgesics combine NSAID or paracetamol with an opioid eg cocodamol
How does aspirin differ from other NSAIDs? What additional effects does it have in cardiovascular disease and what is the mechanism of its action?
The only NSAID to irreversibly inhibit COX enzymes by acetylation. Unique PK profile. T½ less than 30 minutes rapidly hydrolysed in plasma to salicylate.
Aspirin is an antiplatelet drug, it reduces the risk of blood clots forming thus reducing risk of stroke or heart attack.
A 56 year old man with a history of osteo-arthritis presents with increasing pain and swelling in his knees for the last week.
What pain relief could you offer? Describe in stepwise fashion.
Regular paracetamol and/or topical non-steroidal anti-inflammatory drugs should be considered ahead of oral NSAIDs.
If paracetamol or topical NSAIDs insufficient pain relief for OA, addition of mild opioid analgesic eg codeine (consider risks and benefits in older people)
Topical capsaicin considered as an adjunct to core treatments.
Consider oral NSAID/COX-2 inhibitor if paracetamol and topical ineffective – lowest effective dose for shortest possible period, co-prescribe with PPI and
consider cardio-renal and liver toxicity
Intra-articular corticosteroid injections as adjunct for moderate to severe pain in OA
A 56 year old man with a history of osteo-arthritis presents with increasing pain and swelling in his knees for the last week.
You decide to prescribe a NSAID. What other aspects of the medical history would you require from the patient before prescribing a NSAID?
GI health e.g. history of heartburn, gastric bleeding, ulceration (inflammatory bowel disease), cholestasis
Coagulation defects or on anticoagulants
Cardiovascular risk (do not use if severe heart failure, do not use coxibs and diclofenac in people with IHD, peripheral arterial disease, CVD)
Hypersensitivity to aspirin or other NSAIDs
Renal function due to further risk of renal compromise
Drug history, asthma
A 56 year old man with a history of osteo-arthritis presents with increasing pain and swelling in his knees for the last week.
You decide to prescribe a NSAID. What would determine your choice of NSAID?
Extent of pain
Contraindications, topical vs oral
Limitation of ADRs
Cost
A 56 year old man with a history of osteo-arthritis presents with increasing pain and swelling in his knees for the last week.
You decide to prescribe a NSAID. What advice would you give the patient regarding NSAID treatment?
Not to exceed maximum dosage – increased risk of ADRs
Avoid regular use – short term and lowest dose possible
Adjust dose to manage pain within maximum dosage
Observant for ADRs esp GI bleeding, hypersensitivity
Name the three major groups of Endogenous Opioids. Where are they known to occur in the Nervous System?
Three major groups:
- Endorphins
- Enkephalins
- Dynorphins
Distributed in specific parts of the central and peripheral nervous system involved in processing pain signal; the limbic system, thalamus, spinal cord, primary afferent peripheral terminals
Name the three major types of know Opioid Receptor. Which of these is considered to mediate the majority of therapeutic effect?
Mu (μ) Kappa (ĸ) Delta (δ) All G protein coupled receptor sites Majority of therapeutic effects of exogenous opiates mediated via the μ
What is the mechanism by which Opioids exert their effect at the cellular level?
Morphine action on μ, δ and κ opioid receptor (GPCRs) signal through Gi pathway, decreases cAMP and protein kinase A. Opens K-channels which increases K+ efflux and decreases Ca2+ influx through calcium channels.
Lowers resting membrane potential making cells less excitable. Reduces release of neurotransmitters
Name a frequently used Opiate Antagonist: How does this act and when would it be used?
Naloxone
Naltrexone- longer half-life
Reverse opioid toxicity eg heroin overdose or od of pain medication, reverse respiratory depression
(Treatment of dependence – more likely to use methadone in this case)
What are the major ADRs associated with Opiate use?
Nausea, vomiting (most common, particularly in initial stages) always prescribe anti-emetic, constipation, dry mouth and biliary spasm
Large doses – muscle rigidity, hypotension and respiratory depression
Bradycardia, tachycardia, palpitation, oedema, postural hypotension, dizziness, vertigo, mood changes, euphoria, dysphoria, confusion, drowsiness, sleep disturbances, headache, sexual dysfunction, difficulty with
micturition, miosis, visual disturbance, sweating, flushing, rash and urticaria.
Long-term: hypogonadism, adrenal insufficiency (amenorrhoea), reduced libido, infertility, depression and erectile dysfunction
Use in caution in patients with impaired respiratory function (avoid in COPD) and asthma (avoid in acute attack), hypotension
Repeated use is associated with development of psychological and physical dependence.
A 72-year-old man has returned to the ward following an open cholecystectomy. That night, he is complaining bitterly of wound pain once the anaesthesia has worn off.
You prescribe the man 75 mg of pethidine, which greatly improves his symptoms. He thanks you and you return to bed. You are then called by the nurse in charge, who says he has become increasingly drowsy and less responsive.
Describe your initial assessment of the patient?
A B C D E (and blood glucose)
Airway – give 100% high flow oxygen, maintain airway
Breathing – RR (respiration rate: likely hypoventilating, shallow and slow), sats
Circulation – likely hypotensive, bradycardic
Disability – pin-point pupils (note, pethidine can cause mydriatic effect so absence of small pupils should not preclude trial of naloxone) and infrequent/slurred speech
Exposure – opioids can predispose to temperature
Should check BM
A 72-year-old man has returned to the ward following an open cholecystectomy. That night, he is complaining bitterly of wound pain once the anaesthesia has worn off.
You prescribe the man 75 mg of pethidine, which greatly improves his symptoms. He thanks you and you return to bed. You are then called by the nurse in charge, who says he has become increasingly drowsy and less responsive.
What is the most likely cause of his deterioration?
Opiate overdose
Likely if unresponsive, hypoventilation
A 72-year-old man has returned to the ward following an open cholecystectomy. That night, he is complaining bitterly of wound pain once the anaesthesia has worn off.
You prescribe the man 75 mg of pethidine, which greatly improves his symptoms. He thanks you and you return to bed. You are then called by the nurse in charge, who says he has become increasingly drowsy and less responsive.
What can you do to reverse the current situation and what are the risks of your approach?
Naloxone can be given (a competitive antagonist of opioids at mu receptors) given intravenously, usual dose 0.4-2.0mg (can give im stat). Higher doses (up to 10 times recommended, depending on clinical response) may be
required if overdose with partial agonist e.g. buprenorphine.
Has a rapid onset of action, response within a few minutes, can check response and repeat as necessary – give as an infusion & titrate to response. It can precipitate withdrawal symptoms
Naloxone has a short half-life (~1 hr), so may become comatose as the agonist effect of the opioid such as morphine or heroin (often half life 12-24
hours) reasserts as the concentration of opiate antagonist falls. Blocking opioid receptors can produce hyperalgesia in patients suffering from chronic pain
A 72-year-old man has returned to the ward following an open cholecystectomy. That night, he is complaining bitterly of wound pain once the anaesthesia has worn off.
You prescribe the man 75 mg of pethidine, which greatly improves his symptoms. He thanks you and you return to bed. You are then called by the nurse in charge, who says he has become increasingly drowsy and less responsive.
How could you have avoided this situation?
Check drug & anaesthetic charts to see how much opiate has already been given
Check blood tests for hepatic dysfunction
Titrate dose to achieve desired pain relief without overdose
Can give a constant rate infusion of naloxone if opioid action outlasts that of naloxone or give repeated injections, inhaled oxygen
Ensure monitor patient for a prolonged period
A 33-year-old woman recently diagnosed with metastatic carcinoma of the left breast is admitted from oncology clinic for pain control. She is known to have spinal metastases and malignant pleural effusions confirmed by CT scanning. She has severe back pain and some dyspnoea.
What are the best treatment options for this lady’s pain?
In what ways can these be administered to the patient?
WHO pain ladder:
Regular paracetamol
NSAIDs e.g. ibuprofen
Paracetamol or NSAID given regularly will often be sufficient to manage mild pain – but opiates would help dyspnoea as well as pain in this lady and boney
metastases are extremely painful.
Codeine or tramadol if moderate pain
Morphine if previous measures do not control pain (consider renal function)
Alternatives to morphine – transdermal buprenorphine, fentanyl, hydromorphone, methadone or oxycodone (only initiated by palliative care specialists)
Additional options
- Radiotherapy, bisphosphonates and radioactive isotopes of strontium may be useful for bone mets
- Spinal metastases at risk of pathological fracture – percutaneous cementoplasty (e.g. vertebroplasty or balloon kyphoplasty if collapsed) – only to be used as part of treatment if other ways of treating pain not worked,
can relieve pain in 80% of metastatic cancers, requires specialist spinal surgeons
Tap pleural effusion – will help dyspnoea more than pain in this situation
If neuropathic pain – trial tricyclic antidepressant, gabapentin/pregabalin
If nerve compression – increased back pain, sensory/sphincter disturbance or limb weakness treat with high dose dexamethasone and radiotherapy and
refer urgently to oncologist
Nerve blocks or regional anaesthesia (epidural and intrathecal catheters) if localised specific area
A 33-year-old woman recently diagnosed with metastatic carcinoma of the left breast is admitted from oncology clinic for pain control. She is known to have spinal metastases and malignant pleural effusions confirmed by CT scanning. She has severe back pain and some dyspnoea.
Her consultant recommends she be started on regular Morphine Sulphate Tablets (MST) to control her pain once discharged. Describe a suitable schedule for commencing such a drug.
Look at the last 24 hours requirements (longer term if variable). Consider severity of pain, presence of renal impairment, age or frailty
20-30mg daily is safe for opioid naïve patients (40-60mg daily for patients switched from regular weak opioid) - BNF
Zomorph is a modified release (MR) MST 12 hourly, oramorph (immediate release, 4 hourly) for break through pain
If pain occurs between regular doses (i.e. breakthrough) an additional ‘rescue dose’ of immediate release should be given – usually 1/10th to 1/6th of regular 24 hour dose, repeated every 2-4 hours
Consider last 24 hours, take into account rescue doses required – increments shouldn’t exceed more than half or third of daily dose – convert immediate release to modified release.
A 33-year-old woman recently diagnosed with metastatic carcinoma of the left breast is admitted from oncology clinic for pain control. She is known to have spinal metastases and malignant pleural effusions confirmed by CT scanning. She has severe back pain and some dyspnoea.
Her consultant recommends she be started on regular Morphine Sulphate Tablets (MST) to control her pain once discharged.
What side effects would you warn the patient of?
Constipation (prescribe laxatives routinely)
Nausea and vomiting
Feeling dizzy
Respiratory depression and reduced consciousness if overdose (sleepy or confused)
In long term can cause constipation, itching, weight gain, loss of libido and difficulty breathing at night
A 33-year-old woman recently diagnosed with metastatic carcinoma of the left breast is admitted from oncology clinic for pain control. She is known to have spinal metastases and malignant pleural effusions confirmed by CT scanning. She has severe back pain and some dyspnoea.
Her consultant recommends she be started on regular Morphine Sulphate Tablets (MST) to control her pain once discharged.
She asks about the risk of addiction. What would you tell her?
Opioids become less effective with time (tolerance) and can develop
dependence. If stop taking drug suddenly or lower dose too quickly, can get
symptoms of withdrawal e.g. tiredness, sweating, runny nose, stomach
cramps, diarrhoea, aching muscles
Rare for people in pain to become addicted, more common if been addicted
to opioids before or if past medical history of depression and anxiety.
Dependence is no deterrent in control of pain in terminal illness
A 33-year-old woman recently diagnosed with metastatic carcinoma of the left breast is admitted from oncology clinic for pain control. She is known to have spinal metastases and malignant pleural effusions confirmed by CT scanning. She has severe back pain and some dyspnoea.
Her consultant recommends she be started on regular Morphine Sulphate Tablets (MST) to control her pain once discharged.
How must you prescribe the drug on her TTO (“to take out”) medication list for it to be accepted by pharmacy?
It is a controlled drug, therefore bound by legal requirements
Prescriptions for controlled drugs (CD) must be indelible, signed by
prescriber, dated and specify prescribers address.
It must state:
Name and address of patient
Form (and strength) of the preparation
For liquids – total volume in millimetres – both words and figures
For dosage units – number (both words and figures) to be supplied
Total quantity (both words and figures)
The dose
What are the three main therapeutic effects of NSAIS?
- analgesia
- anti-inflammatory
- antipyresis
Primary mode of action of NSAIDs
Cyclo-oxygenase (COX) enzyme inhibition
inhibition of COX-1 and 2.
List three molecules derived from arachidonic acid
collectively known as the eicosanoids. These include the prostanoids: prostaglandins, prostacyclins, thromboxanes
Leukotrienes are also produced but by a different enzymatic pathway
What is the function of COX-2 in inflammation?
COX-2 is induced in inflammatory cells following activation by cytokines. The resulting prostanoids act as inflammatory response mediators.
Why is the mechanism of action considered an exception to the NSAIDS?
Most NSAIDS are COX-2 inhibitors
Aspirin is a notable exception in that it irreversibly inactivates COX-1 and this provides the basis for its effects on platelets
Differentiate the action of NSAIDs on Cox-1 vs Cox-2
Generally NSAID action on COX-1 is rapid and competitive, on COX-2 is slower and often irreversible.
Aspirin irreversible inactivate COX-1
COX-2 inhibition is considered as the site where NSAIDs
exert their therapeutic anti-inflammatory/analgesic effect
how do NSAIDs act as an analgesic?
By reducing synthesis of PGs that sensitise nociceptors to inflammatory mediators, thought to reduce headache pain by cerebral vasodilation mediated by prostaglandins. May also have a secondary effect on PG facilitation of afferent pain signal in spinal cord dorsal horn neurones.
how do NSAIDs act as an anti-inflammatory?
Along with PGs, there are a number of other mediators orchestrating inflammatory response. Therefore NSAIDs will have an effect proportionate to PG involvement (mainly COX-2). Primarily reduce erythema, swelling and
pain response associated with swelling
how do NSAIDs act as an antipyresis medication?
Fever due to bacterial endotoxins trigger macrophage release of endogenous pyrogen Il-1. This stimulates hypothalamic production of PG-E that elevate set point on central ‘thermostat’. NSAIDs reduce PG-E synthesis.
