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Block 1 - Treatment And Prevention Of Illness > Pain - Analgesia > Flashcards

Pain - Analgesia Flashcards

1
Q

Physiological Pain

A
  • Is a protective mechanism
  • Causes avoidance
  • Little to no tissue injury
  • Pain stops once the stimulus is removed
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2
Q

Pathological Pain

A 
 Results from tissue injury
 Inflammation occurs in the area
 Nerve damage
 Release of neurotransmitters with ongoing stimulation of nociceptors
 Can lead to hyperalgesia
 Persists after the stimulus is removed
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3
Q

Organization of the Nervous System

A

draw

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4
Q

3 parts of Physiology of Pain

A

 Nociceptors
 Stimulus Transmission
 Perception

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5
Q

Nociceptors

A

• Nociceptor free nerve endings = pain receptors
High concentration in skin, pleural and peritoneal membranes (cf eg gastrointestinal lining)
High stimulation threshold
Only generate nerve signal under conditions of tissue damage
Physical disruption
Heat, cold
Chemicals, pH

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6
Q

Nociceptors Examples of pain receptors which detect specific stimuli:

A

– Transit Receptor Potential (TRP) channels
» non selective cation channels
» the most important channels to pain are TRPV1, TRPM8, TRPA1
– Bradykinin and Histamine receptors
– P2X and P2Y ATP receptors
» activated by release of ATP from damaged cells
– ASIC - acid sensitive ion channel
» activated by low extracellular pH (eg lactic acid)
» can result from hypoxia or tissue damage

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7
Q

Sensory fibres

A

Myelinated A(gamma) fibres
• Myelinated = rapid signal transmission
• Immediate pain – “sharp”
• Reflex withdrawal

Non-myelinated C fibres
• Much slower signal transmission
• Longer term, diffuse pain
• Protect damaged tissue to allow repair

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8
Q

Perception

A

Somatosensory cortex: Brain knows what part of body hurts

Limbic system: Pain alters emotion

Reticular formation: pain prevents sleep

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9
Q

Physiology of Pain

A
  • Noxious stimuli activate nociceptors, which become sensitized with stimulation, resulting in a lowered stimulation threshold;
  • Damaged cells release substances which stimulate nociceptors and inflammation;
  • Afferent neurons in the spinal cord relay the signal to multiple areas in the brain, resulting in the perception of pain;
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10
Q

Pathology of Pain

A

• Pathological pain is a disease state caused by damage to the nervous system or by its abnormal function.
• Pain-processing mechanisms function abnormally
– Examples: neuropathic pain syndromes
• Nociception is sustained by chronic injury
– Example: arthritis
• Injured or diseased nerve(s)
• Growth of axonal sprouts
• Formation of ectopic foci

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11
Q

Analgesia

A

The absence, or decrease, of pain in the presence of a stimulus that would normally be painful;
Results from inhibiting pain-promoting pathways or promoting pain- supressing pathways

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12
Q

Analgesia - target sites for pain therapies

A

Transduction – translation of the noxious stimulus into electrical activity at the peripheral nociceptor;

Transmission – the propagation of nerve impulses through the nervous system;

Perception – the final conscious subjective and emotional experience of pain.

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13
Q

Analgesics

• Divided into 5 main classes based on mode of action

A 
– Opioids
– Non-steroidal anti-inflammatory drugs
– Local anesthetics
– Alpha2 -adrenoceptor agonists
– Miscellaneous drugs
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14
Q

The pain control system

A

Also called the endogenous analgesic system
- consists of special areas in the brain and spinal cord which when activated can greatly reduce or even completely abolish pain sensation

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15
Q

Key neurotransmitters in descending analgesic pathway:

A

• Endogenous opioid
-receptor agonists
• Noradrenaline and 5HT

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16
Q

Descending Analgesic Pathway forms basis for Analgesic Pharmacology - also Miscellaneous Analgesics

A

• Opioid receptors are major receptors at the periaqueductal gray (PAG), Raphe and dorsal-horn
– modification of nociceptive transmission by inhibition of the spinal dorsal horn cells
– Opioid drugs form a major class of analgesics
• Noradrenaline and 5HT receptors
– Antidepressant drugs act by altering the activity of these monoamine systems
– Useful adjunct-therapy for chronic pain
• Antiepileptics
– Gabapentin, carbamazepine Ca2+ and Na+ channels
• presynaptic inhibition AND
• Activation of descending noradrenergic analgesic pathway
– Useful for treatment of neuropathic pain

17
Q

Analgesics - Opioids

A

• Bind to opioid receptor sites within CNS (mostly µ but also κ)
• Role of opioid receptor
– subtypes m, gamma, k, all GPCR
– Generally, inhibit neuronal activity
– Spinal cord & Thalamus: pain
– Brainstem: respiration, cough,nausea, bp, pupil diameter
– Limbic system: emotional behaviour
• Drugs
– Full agonists: Morphine
– Prodrug: codeine ( 10% metabolized to morphine)
– Mixed agonists/antagonists, partial agonists: buprenorphine, pentazocine
– Are controlled substances requiring special licenses and documentation of usage

18
Q

Opioids (1): Morphine

A

μ opioid receptor agonist
• Indications
– severe pain
• PK
– poor oral bioavailability (25%) so most often administered im or iv although is available for p.o. administration
– controlled release for continual analgesia (because t1/2 = 4 h)
• ADR
– euphoria, respiritory depression, miosis, vomiting,
constipation, lowering of temperature, hypotension
– tolerance & dependence
• Contraindication
– respiratory depression or severe asthma (see ADR)
• Interactions
– potential for all opiate analgesics to have additive effects with other CNS depressants

19
Q

Opioids (3): Buprenorphine

A

– partial u receptor agonist although high potency
(important learning point – potency v efficacy!)
– Less respiratory depression than full agonists
– Indication analgesia: morphine mimetic in untreated patients opiate detoxification: withdrawal in morphine users. Can be used post-operatively to reverse the narcosis of fentanyl while still providing analgesia
– ADR: minimal sedation, respiratory depression
or hypotension, reduced euphoria – less risk of abuse

20
Q

Narcotic analgesics: non-opiates

A

Fentanyl
• non opiate agonist at u receptor
• High lipophilicity allows bioavailability by several routes
• Potency: 100 x more potent than morphine
• PK: fast onset and relatively short duration
• Indication
– post operative analgesia – i.v.
– transdermal “patch” for breakthrough pain (have short half life)
• ADR: hypoventilation

Tramadol
• non opiate agonist at u receptor but also analgesic through other mechanisms (promotes serotonergic and adrenergic activity)
• Indication
– moderate pain
• Caution
– seizure (especially in patients taking SSRI or TCA)
• ADR
– fewer of normal opiate side effects – because analgesia through other mechanisms. Low incidence of respiratory depression & cons

21
Q

Non-steroidal Anti-inflammatory Drugs

NSAIDs

A
  • NSAIDs are weak organic acids with anti-inflammatory, analgesic, and antipyretic properties;
  • The term nonsteroidal distinguishes these drugs from steroids, which, among a broad range of other effects, have a similar eicosanoid-depressing, anti-inflammatory action;
  • Most NSAIDs inhibit the activity of cyclooxygenase-1 and; 2 (COX-1 & 2), thereby the synthesis of prostaglandins and thromboxanes;
  • COX1: gastric protection, vascular homeostasis, platelet aggregation, kidney function
  • COX-2: induced during inflammation and tissue damage
  • The inhibiting COX-2 leads to the anti-inflammatory, analgesic and antipyretic effects and that those NSAIDs also inhibiting COX-1, particularly aspirin, may cause gastrointestinal bleeding and ulcers in large doses;
22
Q

Cyclooxygenase (COX)

A

draw

Prostaglandins do not themselves cause pain, but they sensitise nerve terminals to other agents partly by inhibiting K channels and partly by facilitating 2nd messenger-mediated phosphorylation reactions

23
Q

Functions of prostaglandins

A

• Prostaglandins (PG)
– bind GPCR
– multiple function as local signalling molecules
• Pain
– PGE2 increases sensitivity of nociceptive fibres
• Temperature
– pyrogen → ↑PGE2 synth (leukocyte) →elevates “temp. set point”
(hypothalamus)
• Inflammation
– several roles in inflammatory process
• Gastrointestinal protection (COX-1)
– PGI2
(prostacyclin) inhibits gastric acid secretion
– PGE2
, PGF2 stimulate protective mucous secretion
• Platelet aggregation
• Kidney
– PGE2 and PGI2 maintain renal perfusion- synthesized in response to reduced perfusion
• Vasodilation
– See ADR!

24
Q

Aspirin

A 
• Prototypical NSAID (Bayer 1920)
• Analgesic,
• Antipyretic
• Anti-inflammatory
• Irreversible acetylation of COX-1 & 2
• Indications
– gout, rheumatoid arthritis, headache….
– cardiovascular disease
– colon cancer
• PK
– normal doses -conjugation (liver) & renal excretion t1/2 ~ 4 hr
• ADR
– GI bleeding
– prolonged bleeding (platelet inhibition)
– ~15% patients hypersensitive
• Cautions - avoid before surgery (platelet inhibition)
25
Q

NSAIDS: Propionic acid derivatives

A

• Reversible COX1 & COX 2 inhibitors
• Drugs: ibuprofen, naproxen, ketoprofen (use less commonly)
• Indications
– anti-pyretic, anti-inflammatory, analgesic: eg arthritis, back pain
– little/minor platelet inhibition
• PK - naproxen more potent and longer t1/2 than ibuprofen-less frequent dosing
• ADR
– less GI effects than aspirin but still cause some bleeding,
– risk of bleeding: ibuprofen

26
Q

NSAIDS: Acetic acid derivatives

A 
• Reversibly inhibit COX1 and 2
• Drugs
– indomethacin
• Indications
– anti-pyretic, anti-inflammatory, analgesic: arthritis, gout
• ADR
– GI effects common
– CNS disturbances common
• Caution
– avoid unless other NSAIDS ineffective due to higher bleeding risk
• Contraindication
– severe heart failure
– peptic ulceration
27
Q

NSAIDS:Oxicams

A

• Drugs
– Meloxicam (less commonly used)
» relatively COX-2 selective (~10 fold) – less GI irritation more cardiac risk in human
• Indications
– arthritis, gout
• PK
– Both have long t1/2 which permits once daily dosing

28
Q

COX-2 selective

NSAIDS: “coxibs”

A

• Mechanism: selective COX-2 inhibitors
» reduced effect at COX-1
» lower risk of GI bleeding, no effect on platelets
• Drugs: Celecoxib, Etoricoxib
• PK
– liver metabolism by Cyp 2C9
– t1/2 ~11 hr allows once daily dosing
• Indications
– patients requiring NSAID but at risk of GI toxicity
– arthritis, but not routinely because of risk of long term use
– full analgesia takes 1 week, full anti-inflammatory effect may take 3 weeks
• ADR: nausea, gastric irritation, renal insufficiency
• Cautions
– renal & hepatic impairment
– Long term use linked to MI & stroke
» Rofecoxib (Vioxx), valdecoxib withdrawn
» Recommend low dose for short duration if possible
• Contraindications
– similar to NSAIDS
– allergy to sulfonamide
– ulcerative colitis, Crohn’s disease – worsens bowel inflammation
– ischaemic heart disease, heart failure, vascular disease
• Drug interactions
– Cyp 2C9 inhibitors may increase serum levels (eg fluconazole)

29
Q

Paracetamol

acetaminophen in USA

A

• Analgesic, antipyretic but POOR anti-inflammatory agent
• Mechanism
– Unclear! Poor activity at COX-1 and COX-2
– Probably inhibits PG synthesis in CNS by COX-3
» no effect platelet function, clotting time
• Indications
– Pain. Regular use more effective than “as needed”
» often combined with weak opiates (different mechanisms allow synergy)
– Antipyretic
• ADR
– few if used at normal therapeutic dose (cf NSAIDS)
– does not cause gastric irritation (because of lack of COX-1 activity)
– no evidence of problems in pregnancy
• Cautions
– avoid in patients with hepatic impairment (metabolized in liver)
– Drug most commonly taken as deliberate overdose.
• Drug interactions
– warfarin : increase INR? Mech unclear and evidence contradictory

30
Q

Alpha2

-Adrenergic Agonists

A 
• Stimulation of the alpha2 – adrenoceptors result in sedation, muscle relaxation, and analgesia
• Clonidine 
• Stimulation presynaptic a2 receptors
 Leading to negative feedback;
 Decreases release of additional
 norepinephrine
31
Q

Local anaesthetics

A

Local anaesthetics act by stopping transmission of signals generated by nociceptors
• Block Na+ channels: prevents axonal depolarisation and
formation of action potential

32
Q

Opioids: Codeine

A

• Cyp 3A4 and 2D6 partially demethylate codeine to morphine (hence codeine has lower potency)
• Indications
• antitussive (at dose that aren’t analgesic)
• diarrhoea (see morphine ADR)
• rarely causes dependence
• Often used in combination with aspirin or paracetamol for analgesia – poor analgesics on own
• ADR
– low dose (8 mg)– constipation
– full dose (60 mg) – typical opiate ADR – see above

33
Q

Pain ≠ Nociception

What is the difference?

A

-Pain is a product of higher brain center processing of signals it has received.
-Nociception refers to the peripheral nervous systems processing information generated by stimulation of
nociceptors by noxious stimuli
-Nociception can occur in the absence of pain.

34
Q

Transmission of sensory fibres A and C

A

A(gamma) fibres form direct synapses to ascending fibres
which enter contralateral spino-thalamic tract

C-fibres connect to ascending fibres via connecting interneurons

Block 1 - Treatment And Prevention Of Illness (32 decks)

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