Pain and analgesia

Question 1

what is the World Health Organisations definition of pain?

Answer 1

1) an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage

Question 2

how are patients asked to indicate the degree of pain they are experiencing?

Answer 2

1) Pain scales where patient is asked to indicate degree of pain in relation to extremes
- can be a numerical scale 0 (no pain) to 10 (worse pain)
- Visual Analogue Scale ( mark along the scale)
2) Rating scales: patient asked to indicate degree of pain:
- word descriptor scales ( e.g. 0= no pain, 2 = distressing pain, 5 = excruciating pain…)
- verbal scale (On a scale of 0 to 10…)

Question 3

other scales used to indicate pain are functional and categorical scales. describe these scales

Answer 3

1) functional scales:e.g. 0= no pain, 1 = tolerable and pain does not prevent any activities, 5 = intolerable and pain prevents verbal communication
2) Categorical scale: Mild (1-3) , Moderate (4-6), Severe (7-10)

Question 4

Graphic scales can also be used to rate pain. what are graphic scales and when would they be used?

Answer 4

1) uses smiley faces: 0 = Very happy, no hurt :), 10= Hurts as much as you can imagine :(.
2) used for young/disabled patient

Question 5

list five scales used to indicate pain

Answer 5

1) word descriptor scale
2) verbal scale
3) functional scale
4) Categorical scale
5) graphic scale

Question 6

Pain is multifactorial, but can be divided into 2 broad sub-classes. name the two sub-classes

Answer 6

1) Nociceptive pain

2) Neuropathic pain

Question 7

1) what is Nociceptive pain ?

2) give examples of Nociceptive pain

Answer 7

1) Peripheral visceral or somatic pain due to direct activation of pain-sensing receptors (nociceptors) in response to a noxious stimulus that alerts the organism of impending tissue damage
2) Examples: inflammation, fractures, burns, bumps & bruises

Question 8

what are the two types of Nociceptive pain?

Answer 8

1) acute : lasting < 3-6 months, desirable defence mechanism

2) chronic : lasting >6 months, undesirable

Question 9

1) what is Neuropathic pain ?

2) give examples of Neuropathic pain

Answer 9

1) Pain produced by damage to, or dysfunction of, nerves in the peripheral or central nervous system
2) Examples: trigeminal neuralgia, nerve trauma, peripheral neuropathy, phantom limb pain

Question 10

Is Neuropathic pain chronic or acute?

Answer 10

1) Neuropathic pain tends to be chronic, but can also be acute
(e. g. following surgery)

Question 11

Nociceptive pain perception may be viewed as a three-stage process. outline these 3 stages

Answer 11

1) Detection of pain in the periphery. Noxious stimuli (to skin or subcutaneous tissue) activates sensory nociceptors
2) Transmission of pain signals from the periphery to spinal cord, predominantly by C-fibres and Aδ -fibres. Signals are amplified or inhibited by local neuronal circuits and descending inhibitory pathways from higher brain centers
3) Reception of signal by higher central brain centers, afferent activity generates a pain sensation and initiates an appropriate response

Question 12

Name the three mine types of fibres involved in sensory transduction and state their function.

Answer 12

1) Aβ: touch/pressure (mechanoreception). Likely target of TENS and acupuncture
2) Aδ: signal sharp pain (nociceptors)
3) C: Dull, burning pain (nociceptors)
- Temperature (thermoceptors)

Question 13

state the diameter, conduction velocity and myelination for the following fibres.

1) Aβ
2) Aδ
3) C

Answer 13

1) Aβ: diameter= 5-10ɥm
- conduction velocity (m/s)= 30-70
- myelination: thick
2) Aδ: diameter= 2-5ɥm
- conduction velocity (m/s)= 5-30
- myelination: thin
3) C: diameter= ~1ɥm
- conduction velocity (m/s)= < 1
- myelination: none

Question 14

outline the gate control theory proposed by Melzack and Wall

Answer 14

1) perception of pain may be controlled by a ‘gate
2) The gate is formed by transmission neurones which supply the thalamus and are affected by small inhibitory neurones (substantia gelatinosa SG interneurones) and by nociceptive (C and Aδ fibres) and mechanoreceptor (Aβ) fibre input.

( The smaller, unmyelenated A (delta) and C nerve fibers sense pain such as sharp burning and aching feelings. Larger, myelenated A (beta) skin nerves which carry senses of touch, heat, cold and pressure. the A (beta) nerves are faster, and also have priority which effectively blocks out the pain messages to the brain and closes the gate.) -> google

Question 15

summarise the role of the following in the gate control theory:

1) SG (substantia gelatinosa)
2) C/Aδ fibres
3) Aβ
4) Descending inhibitory pathways from the CNS

Answer 15

1) SG interneurones inhibit (close) the gate: reduce pain
2) Activation of C/Aδ fibres open the gate (increase pain) by: direct excitation of the gate, inhibition of SG interneurones
3) Activation of Aβ fibres close the gate by: excitation of SG interneurones
4) Descending inhibitory pathways from the CNS close the gate by: inhibition of the gate, direct activation of SG interneurones

Question 16

targeting inflationary mediators is the basis for designing analgesic drugs. list the Inflammatory mediators of peripheral pain and state their function.

Answer 16

1) Bradykinin activates :
- B₂ receptors in nociceptive neurones
- B₁ receptors: via the metabolite des-Arg⁹BK; ‘upregulated’ by inflammation
2) Substance P: activate NKA (neurokinin) receptors in nociceptive neurones
3) Adenosine triphosphate (ATP): activate P₂X₃ receptors
4) Protons (H+): activate Acid-Sensing Ion Channels (ASICs)
5) Endogenous activators of TRPV1 vanilloid receptors also heat, target of capsaicin . TRPV1 upregulated by BK and Nerve Growth Factor (NGF)
6) Prostanoids

Question 17

1) what are Prostanoids and when are they released?
2) what do Prostanoids cause?
3) how can the release of these mediators be blocked?

Answer 17

1) Prostanoids are released in inflammation (prostaglandins and thromboxane) produced from precursors in cell membrane
2) cause release of two mediators, PGE2 and PGF2 released in inflammation, greatly increase responses to bradykinin and 5-HT = sensitization (more painful)
3) Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as aspirin block the cyclooxygenase enzyme which breaks down arachidonic acid into all of the above mediators.

Question 18

outline the Important neurotransmitters involved in transmitting Nociceptive pain impulses to higher brain centres.

Answer 18

1) Glutamate (excitatory amino acid) acts at:
- AMPA receptors mediate acute pain (fast response, sets baseline)
- NMDA receptors (delayed response)
2) Substance P (often co-released with glutamate) acts at NK1 (NKA) receptors to enhance NMDA action (hypersensitivity). Often CGRP (peptide) is co-released
3) this leads to Nitric oxide (NO) release which enhances further transmission of pain signal (hyperalgesia)
- positive feedback as NO causes more and more Glutamate to be released

Question 19

1) outline the causes of Neuropathic pain.

2) what does neuropathic pain feel like?

Answer 19

1) Damage to peripheral (neuralgia, neuropathy due to injury or infection eg. shingles) or central (trauma, stroke, MS) nerves.
2) Neuropathic pain may be described as:
severe, sharp, burning, cold, producing numbness, tingling or weakness.
- May be felt traveling along the nerve path from the spine to the periphery.

Question 20

physiologically we dont really know what causes neurophatic pain which is why there is no really good first line therapeutics. discuss some of the ideas behind what causes neuropathic pain

Answer 20

1) Sodium channel clustering: Redistribution of sodium channels to areas of nerve damage can set up ectopic (out of place) firing
2) Sympathetic NS-mediated pain: Upregulation of α-adrenoceptors means that NA release causes pain

Question 21

what is the therapy for Nociceptive pain?

Answer 21

non-opioid (paracetamol, aspirin and other Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)) and opioid analgesics are the main drugs used to treat pain
- Non-opioids are limited by ceiling effect (dose above which there is no further pharmacological action)

Question 22

what is the therapy for Neuropathic pain?

Answer 22

Neuropathic pain (and chronic pain): antidepressants, anticonvulsants, and other CNS-active drugs may also be used and are first-line therapy for some conditions

Question 23

Non-Opioid Drugs such as aspirin and paracetamol can be used together for mild to moderate pain. outline the MOA of aspirin

Answer 23

1) Blocks cyclooxygenase (COX) enzymes: COX-1 and COX-2 (induced at the site of damage) isoforms
2) COX-1 associated with gastroprotection, therefore COX-2-selective drugs (‘coxibs’) sought

Question 24

1) what are NSAIDs used for?

Answer 24

1) acute mild to moderate pain or chronic disease accompanied by pain and inflammation
2) NSAIDs also widely used to prevent blood clots and as anti-pyretic (reduce fever) and anti-inflammatory agents
3) Dose used to treat inflammation is typically higher and time-course is longer (up to 3 weeks) compared to analgesia (~ 1 week)

Question 25

1) what is aspirin indicated for? | 2) what are the disadvantages of using aspirin?

Answer 25

1) Used in headache, transient musculoskeletal pain, dysmenorrhoea (period pain) etc. 2) Due to gastric irritant effects (via COX-1 block) and anti-platelet effects (via TXA2 effect), other NSAIDs typically recommended for analgesia

Question 26

1) what are Non-selective NSAIDs? | 2) give examples of Non-selective NSAIDs

Answer 26

1) inhibit both types of the COX enzyme and thus are associated with an increased risk of gastric ulceration, through reduction in gastric protection and irritation of the gastric lining 2) Indoles: diclofenac or indomethacin - Propionic acid derivatives: ibuprofen, naproxen and ketoprofen

Question 27

1) what are the benefits of COX-2 selective NSAIDs ‘coxibs’? 2) give examples of COX-2 selective drugs and their indication 3) what are the disadvantages of these drugs?

Answer 27

1) Selective COX-2 inhibitors directly targets COX-2. Targeting selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug class. 2) Celecoxib and etoricoxib are licenced in the UK to treat pain in osteoarthritis and rheumatoid arthritis and ankylosing spondylitis; etoricoxib is also licensed for the relief of pain from acute gout. 3) All carry a warning for cardiovascular risk.

Question 28

what is Nefopam?

Answer 28

Nefopam is a non-opioid analgesic which can be used for persistent pain if NSAIDs are not effective. Causes little or no respiratory depression (associated with opioids), but can have sympathomimetic and antimuscarinic side-effects.

Question 29

Paracetamol is a non-opioid drug, lacks anti-inflammatory effects and so is not an NSAID. outline the MOA of paracetamol

Answer 29

1) Paracetamol is an effective analgesic believed to work by reducing the production of prostaglandins in the brain and spinal cord 2) Mechanism of action: TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol.

Question 30

1) what are compound analgesics? | 2) list some compound analgesic preparations

Answer 30

1) Combination of a non-opioid (such as aspirin or paracetamol) with an opioid to manage of pain of varying intensity. 2) - Co-codamol 8/500 (8 mg codeine phosphate:500 mg paracetamol) [p] - Co-codamol 30/500 [POM]: effective in more severe pain, but accompanied with opioid side effects - co-dyramol: paracetamol with dihydrocodeine tartrate)

Question 31

1) What are opioids? | 2) give examples of opioid receptor agonists

Answer 31

1) Opioids are morphine-like drugs whose effects are blocked by naloxone, act spinally and supra-spinally to produce analgesia in moderate to severe pain (post-operative, cancer pain) 2) agonists : Morphine, Pethidine, Methadone - Naloxone (antagonist) - Opioids are agonists which inhibit presynaptic receptors = block pain signals

Question 32

name the 4 opioid receptor subtypes and state their endogenous agonists.

Answer 32

1) delta (δ): β-endorphin enkephalins 2) kappa (k): β-endorphin dynorphins 3) mu (μ): β-endorphin, endomorphins 4) N/OFQ Nociceptin / orphanin FQ: nociceptin

Question 33

state the therapeutic agonists for each of the following receptors: 1) kappa (k) 2) mu (μ)

Answer 33

1) kappa (k):pentazocine | 2) mu (μ): morphine, codeine, fentanyl, pethidine etc

Question 34

what is the MOA of opioids?

Answer 34

1) Spinal action:Activate pre-synaptic μ > δ receptors to reduce transmitter release 2) Supra-spinal action: Opioid action at μ (δ and k) receptors enhance descending inhibitory pathway in brain stem/midbrain involving NA and 5-HT release (by blocking GABA inhibition)

Question 35

discuss the clinical uses of opioid agonists

Answer 35

All act at δ receptors (except pentazocine, k agonist) used to treat all forms of severe nociceptive pain eg. accidents, pre-, post-operative pain, cancer pain; reportedly less useful in neuropathic pain

Question 36

discuss the use of morphine therapeutically

Answer 36

1) Morphine: ‘gold standard’ to which all opioids are compared. 2) reduces the affective component of pain 3) metabolised to potent analgesic morphine-6-glucuronide 4) dose typically titrated against amount of pain relief commonly given IV or orally as morphine sulphate tablets (MST)

Question 37

opioid drugs Differ only in potency and pharmacokinetics. state the indication of the following opioids: 1) Fentanyl 2) Pethidine 3) Oxycodone 4) Dihydrocodeine 5) Tramadol

Answer 37

1) Fentanyl: very potent, short-duration, often used as a transdermal patch 2) Pethidine: used during labour (due to lack of effect on uterine contraction) 3) Oxycodone: used primarily for control of pain in palliative care. 4) Dihydrocodeine: similar efficacy to codeine - can cause more nausea and vomiting 5) Tramadol: weak opioid and an inhibitor of the noradrenaline uptake/transport system

Question 38

name an opioid drug which is a partial agonist

Answer 38

Buprenorphine: long duration, can be given sublingually

Question 39

what are the benefits of using low dose codeine and what are the disadvantages?

Answer 39

1) Codeine: low efficacy, orally effective drug. Not addictive, so widely used for mild pain such as back-, head- and toothache 2) causes constipation with long-term use

Question 40

discuss the Side-effects of opioid agonists

Answer 40

1) Respiratory depression: reduces sensitivity of respiratory centre; most common cause of death from overdose with street use of opioids; treated with naloxone. 2) Euphoria: action on reward pathway in the brain to increase dopamine release 3) Cough suppression (anti-tussive): can be therapeutically useful 4) Nausea: activate the chemoreceptor trigger zone (which in turn activates the vomiting centre) - anti-emetics typically co-prescribed 5) Constipation: due to maintained contraction of smooth muscle (Kaolin & Morphine used as an anti-diarrheal agent)

Question 41

Opioids and NSAID’s are usually not that effective for Neuropathic pain. Treatments for neuropathic pain include a variety of drugs generally used for chronic pain. list some of these drugs

Answer 41

1) Antiepileptic drugs: Carbamazepine, phenytoin (sodium channel blockers) and gabapentin, pregabalin (via effects on calcium channels) 2) Tricyclic antidepressants: Duloxetine and imipramine/amitriptyline effective in conditions such as in diabetic neuropathy 3) Ketamine: due to block of NMDA receptors 4) Lidocaine or bupivacaine: Local anaesthetics which block sodium channels when injected close to a sensory nerve 5) Ziconotide: administered intrathecal infusion to treat neuropathic pain 6) Cannabinoid agonists: Sativex- licenced in UK to treat pain in multiple sclerosis patients.

Question 42

describe the WHO pain ladder

Answer 42

If pain occurs, there should be prompt oral administration of drugs in the following order: 1) non- opioids (aspirin and paracetamol); then, as necessary, 2) mild opioids (compound analgesic or weak opioid) 3) then strong opioids such as morphine, until the patient is free of pain.

Question 43

what are the treatment options for the following: 1) Musculoskeletal and dental pain, period pain 2) Mild, inflammatory pain (sprains) 3) Severe, acute pain 4) Severe, chronic pain 5) Neuropathic pain generally unresponsive to opioids

Answer 43

1) paracetamol or NSAIDs 2) co-codamol, codeine, dihydrocodeine 3) strong opioid IV- morphine, fentanyl 4) treated by oral, intrathecal or subcutaneous strong opioid-morphine, fentanyl 5) amitripyline, pregabalin