- Signalling system - mechanical and nerve - Unpleasant sensory and emotional experience - Perception (independent of person experiencing it) - No objective measuring system - Symptom of underlying disease/injury (bodies warning system) Pain is the activation of pain receptors - A delta and C sensory fibers - May be due to misfiring/dysfunction of nerves

Opioids - MOA - Pharmacological effects - Unwanted effects

MOA - Act on opioid receptor on neuronal cell membrane in CNS and PNS (specifically mu receptor) - Mimic endogenous opioid such as b endorphin to reduce transmission of pain impulse - Produce analgesia, respiratory depression, sedation and constipation - Reduce transmission of pain impulse by acting pre and post synaptically in spinal cord and by modulating descending inhibitory pathway from brain Pharmacological effects - Analgesia/cough suppression/antidiarrheal (codeine) Unwanted effects - Analgesic tolerance - Physical dependence - Respiratory depression - Constipation - Nausea, vomiting, sedation (tolerance often develops)

Strong opioids - morphine - ADR - Contraindications and cautions

- Morphine is benchmark for comparing opioid equivalence - Stronger opioids have higher affinity and/or efficacy for opioid receptors - Higher incidence of ADR including sedation, respiratory depression, GI effects, addiction/dependence and tolerance Contraindications and cautions - Elderly (reduce dose and titrate slowly) - Hepatic impairment (Avoid in severe) - Children (avoid in neonates, only when indicated by specialist in older children) - Pregnancy (caution close to delivery) - Breastfeeding (avoid repeated doses) - Renal impairment (reduce dose in mild/mod and avoid in severe) - Contraindicated in comatose, endocrine abnormalities, epilepsy and hypotension

Non opioid analgesics - Indications - Causes

``` Indications - Neuropathic pain (described as burning, electric shock, shooting pain) > Hyperalgesia > Allodynia > Hyperpathia ``` Causes - Phantom limb pain - Diabetic neuropathy - Postherapetic neuralgia - Herpes zoster - Fibromyalgia

Paracetamol - Class - Indication - MOA - Practice points

Class - Analgesic and antipyretic Indication - 1st line for mild to mod pain in several situation - Well tolerated MOA - Analgesia MOA may include inhibition of central prostaglandin synthesis and possible effect on serotonergic pain pathways - Antipyretic effect probably due to reduced production of prostaglandins - Negligible anti-inflammatory effects Practice points - Hepatotoxicity with excessive use and overdose - Increase risk of adverse effects in hepatitis or chronic alcohol use - Works best taken regularly at max recommended dose (especially chronic) - Safe for children approx 4 weeks - Safe for pregnancy and breastfeeding - Dangerous in large overdose (liver failure and death)

NSAID - MOA - Practice points - Contraindications

MOA - Inhibit synthesis of prostaglandins by inhibiting cyclo-oxygenase (COX) 1 and 2 See diagram Practice point - Non is more effective than other - Dependent on patient response Contraindications (many) - CVD - Asthma - Therapy with anticoagulants - Renal impairment - Dehydration - PUD/GORD/GIT complication - Elderly - Pregnancy - Impending surgery

Week 10: Pain and Musculoskeletal - Opioids, Non opioids, NSAIDs, Arthritis Flashcards by Caitlyn Ryan

What is pain?

Signalling system - mechanical and nerve
Unpleasant sensory and emotional experience
Perception (independent of person experiencing it)
No objective measuring system
Symptom of underlying disease/injury (bodies warning system)

Pain is the activation of pain receptors

A delta and C sensory fibers
May be due to misfiring/dysfunction of nerves

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Classification of pain

Acute and chronic
Types of pain

Acute
- Usually has anxiety and hyperactivity of SNS causing tachycardia, increased respiratory rate and increased blood pressure

Chronic
- Usually no sympathetic hyperactivity and may have depressed mood, fatigue, loss of appetite

Types of pain:
Nociceptive
- Pain related to damage of somatic or visceral tissue due to trauma or inflammation
- Examples = rheumatoid arthritis, osteoarthritis, gout

Non-nociceptive Neuropathic pain

Pain related to damage of peripheral or central nerves
Examples = painful diabetic peripheral neuropathy, postoperative neuralgia

Sensory hypersensitivity

Pain without identifiable nerve or tissue damage
Thought to result from persistent neuronal regularization
Examples = fibromyalgia

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Non pharmacological management of pain

PT/OT
CBT, meditation, counseling
Mobility aids
Heat
Rest
Ice
Compression
Elevation

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Treating pain - WHO analgesic ladder

Step 1

Non opioid +/- adjuvant
E.g. aspirin, paracetamol or NSAID

Step 2:

Weak opioid for mild to moderate pain +/- nonopioid +/- adjuvant
E.g. codeine

Step 3

Strong opioid for moderate to severe pain +/- non opioid +/- adjuvant
E.g. morphine

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Opioids

MOA
Pharmacological effects
Unwanted effects

MOA

Act on opioid receptor on neuronal cell membrane in CNS and PNS (specifically mu receptor)
Mimic endogenous opioid such as b endorphin to reduce transmission of pain impulse
Produce analgesia, respiratory depression, sedation and constipation
Reduce transmission of pain impulse by acting pre and post synaptically in spinal cord and by modulating descending inhibitory pathway from brain

Pharmacological effects
- Analgesia/cough suppression/antidiarrheal (codeine)

Unwanted effects

Analgesic tolerance
Physical dependence
Respiratory depression
Constipation
Nausea, vomiting, sedation (tolerance often develops)

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Weak opioids

Codeine (metabolism, contraindications and cautions)
Dextropropoxyphene

Codeine
- Metabolised by kidney to morphine
- Not proven to be effective at OTC dosages (prescription only)
- Contraindications and cautions
> Elderly (reduce dose due to increase risk of cognitive impairment, sedation, respiratory depression and falls)
> Hepatic impairment (reduce dose and monitor)
> Children (usually contraindicated under 12 use with caution)
> Pregnancy (caution close to delivery)
> Breastfeeding (Do not use)
> Renal impairment (avoid)
> Contraindicated in comatose, epilepsy, hypotension, shock and neonates

Dextropropoxyphen

Lots of ADR
Prescribe must write special application

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Examples of strong opioids

Tramadol
Fentanyl
Morphine
Hydromorphone
Oxycodone
Pethidine
Methasone (for opioid addiction)
Buprenorphine (partial agonist - longer onset of action)

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Strong opioids - Tramadol

MOA
Contraindications and cautions

MOA

Technically not an opioid
Structurally not opiate but exhibits opioid characteristics
Binds mu receptor but 10 time less affinity than codeine
Inhibits reuptake of NA and 5HT

Contraindications and cautions

Elderly (avoid over 75; avoid CR)
Hepatic impairment (reduce dose in severe impairment; avoid CR)
Children (avoid use except under specialist)
Pregnancy (caution close to delivery)
Breastfeeding (avoid)
Renal impairment (avoid CR)
Contraindicated within 14 days of stopping MAOI or other serotonergics
Same contraindications as codeine

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Strong opioids - morphine

ADR
Contraindications and cautions

Morphine is benchmark for comparing opioid equivalence
Stronger opioids have higher affinity and/or efficacy for opioid receptors
Higher incidence of ADR including sedation, respiratory depression, GI effects, addiction/dependence and tolerance

Contraindications and cautions

Elderly (reduce dose and titrate slowly)
Hepatic impairment (Avoid in severe)
Children (avoid in neonates, only when indicated by specialist in older children)
Pregnancy (caution close to delivery)
Breastfeeding (avoid repeated doses)
Renal impairment (reduce dose in mild/mod and avoid in severe)
Contraindicated in comatose, endocrine abnormalities, epilepsy and hypotension

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Opioid overdose and dependence

- Naltrexone

Opioid overdose can be hard to treat due to severe withdrawal symptoms
> Use methadone in step wise manner

Naltrexone - opioid antagonist

Reversibly blocks effects of opioid for 24-72 hrs
After it wears of patient more susceptible to effects of opioids (fatal overdose)

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Non opioid analgesics

Indications
Causes

Indications
- Neuropathic pain (described as burning, electric shock, shooting pain)
> Hyperalgesia
> Allodynia
> Hyperpathia

Causes

Phantom limb pain
Diabetic neuropathy
Postherapetic neuralgia
Herpes zoster
Fibromyalgia

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Non opioid analgesic treatment options

Neuropathic pain treatment options

Paracetamol
Topical capsaicin
Antidepressant - may inhibit nociceptive transmission via inhibition of NA and 5HT reuptake (TCA, SSRI, SNRI)
Antiepileptic - decrease excitability of neurons by modifying action of voltage gated Ca2+ channels - reduced release of P, NA, and glutamate (gabapentin, pregabalin)

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Local anaesthetics

MOA
Examples
Practice points

MOA

Block sodium channels in order to reversibly interrupt peripheral nerve impulse conduction
Block ability of nerve cell to depolarise and send pain signals to CNS

Examples

Lignocaine
Prilocaine
Cocaine

Practice points

All cause vasodilation, which can make drug leak into surrounding tissue, limiting duration of action
Usually given along with adrenaline (powerful vasoconstrictor) to keep anaesthetic localised and increase duration of action

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Paracetamol

Class
Indication
MOA
Practice points

Class
- Analgesic and antipyretic

Indication

1st line for mild to mod pain in several situation
Well tolerated

MOA

Analgesia MOA may include inhibition of central prostaglandin synthesis and possible effect on serotonergic pain pathways
Antipyretic effect probably due to reduced production of prostaglandins
Negligible anti-inflammatory effects

Practice points

Hepatotoxicity with excessive use and overdose
Increase risk of adverse effects in hepatitis or chronic alcohol use
Works best taken regularly at max recommended dose (especially chronic)
Safe for children approx 4 weeks
Safe for pregnancy and breastfeeding
Dangerous in large overdose (liver failure and death)

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Overdose of paracetamol

- Factors increasing risk of hepatotoxicity

Factors increasing risk of hepatotoxicity due to paracetamol

Increased frequency of dosing
Using higher than recommended doses for prolonged period
Malnourished or dehydrated
Fasting or vomiting
Taking with other drugs such as antiepileptics

Common cause of paracetamol induced liver damage is inadvertently taking 2 paracetamol containing preparations at once

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NSAID - Non steroidal anti inflammatory drugs

Effects
Examples

Effects

Analgesic
Antipyretic
Anti inflammatory

Examples

Aspirin
Ibuprofen
Diclofenac
Naproxen
Indomethacin

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NSAID

MOA
Practice points
Contraindications

MOA
- Inhibit synthesis of prostaglandins by inhibiting cyclo-oxygenase (COX) 1 and 2
See diagram

Practice point

Non is more effective than other
Dependent on patient response

Contraindications (many)

CVD
Asthma
Therapy with anticoagulants
Renal impairment
Dehydration
PUD/GORD/GIT complication
Elderly
Pregnancy
Impending surgery

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NSAIDS - Cox Enzymes

Cox 1
Cox 2

Cox 1

Expressed in most tissue and responsible for synthesis of protective mucosal prostaglandins in GIT to maintain normal lining of stomach
Also involved in kidney and platelet function

Cox 2

Expressed in many tissues including brain, kidney, placenta, GIT
Induced during inflammation and tissue repair
May have significant role in renal function

Selective NSAIDs

MOA
Examples
Practice points

MOA

Selective inhibitors of COX2
Maintain protective mechanisms of COX1 on GIT leading to fewer GIT side effects

Examples

Celecoxib
Meloxicam

Practice points

May have higher incidence of CVD events
Contraindicated in GORD/PUD however, preferred over NSAIDs

NSAID drug interactions

Many between prescription, OTC and complementary medicines
Include
> Warfarin
> ACE inhibitor
> Diuretic
> Sartans
> Lithium
> MTX
> Corticosteroids

Triple Whammy drug interaction

Diuretics - decreased plasma volume therefore reduced renal plasma flow

ACE-I - efferent arteriole dilation which decreases GFR

NSAID - block prostaglandin production which decreases glomerular perfusion

What is osteoarthritis?

Definition

Metabolically active, ongoing process of degradation and synthesis involving different tissue types within effected joint (cartilage, bone, synovial, ligaments and muscle)
Involves inflammation (mild to moderate and at least intermittently)
As OA progresses cartilage synthesis disrupted by inflammation
Synovial fluid starts to thin resulting in loss of joint lubrication and impaired ability to withstand weight bearing load
Eventually cartilage and bone exposed and become damaged

Presentation of OA

General
Symptoms
Pain
Signs

General

Patients generally over 50
Spectrum of symptoms with diagnosis ranging from asymptomatic to severe joint pain and stiffness with limitation to daily function
Joint involvement has asymmetrical distribution without systemic symptoms

Symptoms

Cardinal symptoms are use related pain described as deep, aching, stiff
Advanced cases can present during rest
Weight bearing joints hindered by instability
Stiffness generally lasts <30 min, limits range of joint motion, impairs daily activity and related to weather
Psycho social aspect - depressed mood, loss of independence, anxiety

Pain
- Either acute by active inflammatory process or chronic resulting from peripheral and central sensitization

Signs

Joints in asymmetrical pattern
Common sites (distal finger, proximal finger, wrist, knee, hip, lower spine, big toe

Risk factors of OA

Systemic factors affecting joint vulnerability

Increased age
Female
Genetic
Nutritional factors

Intrinsic joint vulnerabilities

Previous damage
Bridging muscle weakness
Increase bone density
Malalignment
Proprioceptive deficiencies

Use/loading factors

Obesity
Injury from physical activity

Management of OA | - Goals

Goals - Education - Pain control - Maintaining or restoring mobility - Minimize functional impairment - Altering disease process and consequences - Improve QALY

Management of OA | - Non pharmacological

- Weight reduction - Exercise program - Physiotherapy - Thermotherapy - TENS - Acupuncture - Surgery - Insoles - Splints/wraps - Mobility aids

Management of OA | - Drug therapy 1st line

Paracetamol - Regular divided doses - Background therapy - Controlled release option

Management of OA | - Drug therapy 2nd line

NSAIDS - Lowest effective dose due to ADRs - Topical or oral (rubs useful for many patients) - Only use intermittently (before/after exercise or during flare of inflammation - Should be on paracetamol for regular relief

Management of OA | - Drug therapy 3rd line

Opioids - Only if 1st/2nd line don't work or contraindicated - Always start with weak opioid

Management of OA | - Alternative therapy

- Intra-articular corticosteroid injection | - Usually used if one large joint effected

What is rheumatoid arthritis?

Definition - Degenerative, autoimmune disorder that attacks joints and associated tissue as well as other body systems - Leads to inflammation of tissues - Tends to effect smaller bones - Significant morbidity and mortality

Pathophysiology of RA

Autoimmune of antibodies against joints, connective tissue and supporting muscles - Recruitment of B cell and T cells - Release of inflammatory mediators (cytokines) - Results in synovial hypertrophy - Chronic joint inflammation

Risk factors of RA

- Genetic link - HLA DR4 - Age - Female - Lifestyle - Infection (periodontal) - Nulliparity

RA symptoms and presentation

Mostly effects joints - Pain/aching in more than one - Stiffness - Tenderness - Bilateral symptoms - Weight loss - Fever - Fatigue - Weakness

RA complications

- Bony erosion - Degradation of cartilage and tendons - Joint deformity - CVD (HT, hyperlipidaemia, hypercholesterolemia) - Diabetes - Obestiy

Ra treatment | - Non pharmacological

- Lifestyle modification - Heat/cold packs - Orthotics, splints - PT/OT - Daily living aids

RA treatment | - Pharmacological

Begin treatment at once - Paracetamol - NSAIDs/corticosteroids - Antirheumatic tx > Mild disease (sulfasalazine, hydroxychloroquine, corticosteroids) > Moderate disease (low dose MTX, cytokine modulators, leflunomide) Very individualized treatment - requires referral to specialist

RA treatment 1st line - csDMARDs - Examples

Conventional synthetic disease modifying antirheumatic drugs Examples - MTX - Leflunomide - Sulfasalazine - Hydroxychloroquine While waiting for these to have effect or during flare consider corticosteroids

``` RA treatment 1st line - csDMARDs (methotrexate) - MOA - Effects - Practice points ```

MOA - Folic acid antagonist - stops conversion of inactive folic acid to active form folinic acid by antagonising enzyme DHFR - Reducing folinic acid inhibits DNA synthesis Effects - Cytotoxic - Immunosuppressive - Anti-inflammatory Practice points - Oral tablet - only take one day per week - Hepatotoxic - Tetratogenic

RA treatment 1st line - csDMARDs (methotrexate) - Contraindication and cautions

Hepatic impairment - Contraindicated as it is hepatotoxic Children - Under specialist Pregnancy - Avoid as tetratogenic Breastfeeding - Avoid Renal impairment - Contraindicated in mod to severe impairment Avoid in those with immunodeficiency, GI ulcers, UC, active infections

RA treatment 1st line - csDMARDs (methotrexate) - ADR

- Nausea and vomiting - Blurred vision - Oral mucositis - Pulmonary toxicity - dyspnoea, chest pain, cough, fever - Hepatoxicity - Rash/itch/photo sensitivity - Neurotoxicity - Myelosuppression - Immunosuppression

RA treatment 2nd line - bDMARDs - Examples

Biological disease modifying antirheumatic drugs Examples - Abatacept - Adalimumab - Certolizumab - Etanercept - Infliximab Begin combining treatments - Individualized concerning what can be tolerated, severity of symptoms and comorbidity

RA treatment 2nd line - bDMARDs (Infliximab) - MOA - Effects/administration

MOA - TNF alpha antagonist blocking he cytokine stops the inflammatory and immune response Effects/administration - Usually used with MTX - Only IV administration - Lots of ADR - Can take 12 weeks to see effect - Given every 6-8 weeks once reach maintenance dose

RA treatment 2nd line - bDMARDs (Infliximab) - Contraindication and cautions

Hepatic impairment - Hepatoxic - avoid Children - Not indicated in juvenile RA Pregnancy - Avoid Breastfeeding - Specialist advice Cannot be given with certain vaccination Contraindicated if malignancy in last 5 yrs, active infection, blood dyscrasias, heart failure, MS, lupus