pain and analgesia

Question 1

what is pain?

Answer 1

Pain is a subjective experience
Sensory discriminative: Location, intensity, threshold
experience associated with, or resembling that associated with actual or potential tissue damage (IASP, 2020)
important alert system

Question 2

what is acute pain
examples

Answer 2

< 12 weeks
Acute pain is a protective mechanism
broken bones
surgery
dental work
labor and childbirth
cuts
burns
- to ensure healing

Question 3

how can you rate pain

Answer 3

Numeric Rating Scale
Visual Analog Scale (VAS)
Verbal Pain Intensity Scale
(young/disabled patients

Question 4

functional scale

Answer 4

0 = no pain
1 = tolerable and pain does not prevent any activities
2 = tolerable and pain prevents some activities
3 = intolerable and pain does not prevent use of telephone, TV viewing or reading
4 = intolerable and pain prevents use of telephone, TV viewing or reading
5 = intolerable and pain prevents verbal communication

Question 5

what is chronic pain

Answer 5

“Pain in one or more anatomic regions that persists or recurs for longer than three months and is associated with significant emotional distress or significant functional disability”

Question 6

types of chronic pain?

Answer 6

Nociceptive/Inflammatory
e.g., osteoarthritis, post-operative pain,
rheumatoid arthritis

Neuropathic
e.g., nerve injury,
multiple sclerosis, stroke, amputation, neuropathies

Nociplastic
e.g., fibromyalgia,
irritable bowel syndrome

Question 7

what is NOCICEPTIVE / INFLAMMATORY PAIN
examples

Answer 7

• tissue injury

Aches and sprains (back pain)
Arthritis
Cancer pain
Post-operative pain
Headache

Nociceptive pain may be
acute : lasting < 3 months, desirable defence mechanism
chronic : lasting >3 months, undesirable, lack of warning function, beyond normal healing

Question 8

what is Allodynia

Answer 8

Pain after stimulation which is not normally painful

Question 9

what is Hyperalgesia

Answer 9

Increased pain from a stimulus that normally provokes pain.

Question 10

what is NEUROPATHIC PAIN
examples

Answer 10

Damage to peripheral (neuralgia, neuropathy due to injury or infection) or central (trauma, stroke, MS) nerves
Neuropathic pain can be intermittent or constant, and spontaneous or provoked.

Neuropathic pain may be described as:
severe, sharp, burning, cold, producing numbness, tingling or weakness.

Neuropathic pain is a major health problem that affects a significant number of patients, resulting in personal suffering, reduced productivity and substantial health care costs.

Diabetic neuropathy
Phantom limb pain
Cancer pain
Chemotherapy-induced peripheral neuropathy
Postherpetic neuralgia

Question 11

NOCIPLASTIC PAIN

Answer 11

Mechanisms not entirely understood

”Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain” (IASP, 2017)

Patients can have a combination of nociceptive and nociplastic pain

Observed symptoms:
multifocal pain that is more widespread or intense, or both;
fatigue, sleep, memory, and mood problems.

Fibromyalgia,
Complex regional pain syndrome type 1,
Irritable bowel syndrome

Question 12

what is chronic pain

Answer 12

Pain that persists past normal healing time: post surgical pain; migraine.

It lasts or recurs for longer than 3 months.

Question 13

pain control mechanism (treatment options)
acute treatment
preventive treatment

Answer 13

Acute treatment: symptoms of pain (e.g., anti-inflammatory to stop a single headache attack, opioid to reduce post-surgical pain)

Preventive treatment: underlying disorder (e.g.; mirror therapy in phantom limb syndrome

Aspirin and other NSAIDS
Morphine and other opioid/cannabinoids

Question 14

diff between chronic secondary pain and chronic primary pain

Answer 14

both can last over 3 months
can happen together

Chronic Primary Pain
Widespread Pain (fibromyalgia)
Complex regional pain syndrome
Primary headache
Irritable Bowel syndrome
Musculoskeletal pain
(nonspecific low-back pain)

Chronic Secondary Pain
Cancer Pain
Post surgical Pain
Visceral Pain
Neuropathic pain
Headache and orofacial pain

Question 15

Nociceptive pathway

Answer 15

1.Detection of pain in the periphery.
Noxious stimuli (to skin or subcutaneous tissue) activates nociceptors

2. Transmission of pain signals from the periphery to spinal cord,
   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 16

Peripheral nerves contain small and large diameter ‘primary afferent’ fibers

what are there names (3) what is the use?

Answer 16

Medium diameter MYELINATEDfibers (Ad) mediates acute, well-localised or fast pain

Small diameter UNMYELINATEDfibers (C),convey poor localised or slow pain​

Large diameter MYELINATED fibers (Non-nociceptive) (Ab) Touch, pressure

Unmyelinated and small myelinated fibers only respond to noxious (‘painful’) stimulation

But in the setting of tissue injury, these nerve fibers will respond to innocuous stimuli

NON-PAINFUL STIMULI HURT!

Question 17

what are the Inflammatory mediators of peripheral pain

Answer 17

1. Bradykinin (produced from precursors in the vasculature) 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. Prostaglandins, in particular, PGE2 and PGF2 released in inflammation, greatly increase responses to bradykinin and 5-HT = sensitization

Question 18

what are prostanoids?

Answer 18

Prostanoids (prostaglandins and thromboxane) produced from precursors in cell membrane

In particular, PGE2 and PGF2 released in inflammation, greatly increase responses to bradykinin and 5-HT
= sensitization

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as aspirin block the cyclooxygenase enzyme

Question 19

what are the important neurotransmitters -
Nociceptive pain is due to excessive peripheral stimulation;
inflammatory mediators cause hyperalgesia

Answer 19

1) Glutamate (excitatory amino acid) acts at:
AMPA receptors mediate acute pain (fast response, sets baseline)
NMDA receptors (delayed response)

2) Substance P (peptide) acts at NK1 (NKA) receptors to enhance NMDA action (hypersensitivity). Often CGRP (peptide) is co-released; leading to…..

3) Nitric oxide (NO) release which enhances further transmission of pain signal (hyperalgesia)

Question 20

what can be given for pain therapy?

Answer 20

Nociceptive pain: 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 21

what are the Pain therapy: non-opioid drugs
COX - inhibitors

Answer 21

• aspirin
  -ibuprofen

Question 22

what is cox-1 and 2

Answer 22

COX-1
Constitutive enzyme
Expressed in most tissue
‘housekeeping’ role

COX-2
Inducible enzyme
Production of mediators of inflammation

Question 23

when is NSAID used for pain therapy?
examples

Answer 23

Used for
acute mild to moderate pain
chronic disease accompanied by pain and inflammation
NSAIDs also widely used to prevent blood clots and as anti-pyretic (reduce fever) and anti-inflammatory agents

Aspirin (acetylsalicylic acid)
Used in headache, transient musculoskeletal pain, dysmenorrhoea (period pain) etc.

Non-selective NSAIDs:
Indoles: diclofenac or indomethacin
Propionic acid derivatives: ibuprofen, naproxen and ketoprofen

Question 24

when is NSAID used for pain therapy?
examples

Answer 24

Used for
acute mild to moderate pain
chronic disease accompanied by pain and inflammation
NSAIDs also widely used to prevent blood clots and as anti-pyretic (reduce fever) and anti-inflammatory agents

Aspirin (acetylsalicylic acid)
Used in headache, transient musculoskeletal pain, dysmenorrhoea (period pain) etc.

Non-selective NSAIDs:
Indoles: diclofenac or indomethacin
Propionic acid derivatives: ibuprofen, naproxen and ketoprofen

Question 25

NSAIDs ‘coxibs’ used for ?
what cox selective are they?

Answer 25

COX-2 selective

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.

Rofecoxib (Vioxx) and valdecoxib (Bextra) withdrawn due to cardiovascular side-effects. In Nov 2007, the Medicines and Healthcare products Regulatory Agency (MHRA) also withdrew lumiracoxib due to hepatotoxicity problems.

All carry a warning for cardiovascular risk

Question 26

what are NSAIDs adverse effects

Answer 26

To prevent GIadverse effects associated with NSAIDs:
An alternative analgesic should be considered.
Prescribing more than one NSAID at a time should be avoided.
Concomitant use of an NSAID with low-dose aspirin should be avoided
Short-acting NSAIDs (such as ibuprofen) should be used in preference to long-actingformulations (such as naproxen).

For people at:
High riskofGI adverse events:aCOX-2 inhibitor should be prescribed with a proton pump inhibitor (PPI).
Moderateriskof GI adverse events: a COX-2 inhibitor should be prescribed alone, or an NSAID plus a PPI.
Low riskof GI events — a non-selective NSAID should be prescribed.

Question 27

what does Non-opioid drugs: Nefopam used for
(pain therapy)

Answer 27

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

Question 28

what is paracetamol used for
(pain therapy)

Answer 28

Paracetamol is an effective analgesic believed to work by reducing the production of prostaglandins in the brain and spinal cord

Paracetamol lacks anti-inflammatory effects and so is not an NSAID (also lacks anti-platelet action and does not cause gastric irritation)

The paracetamol metabolite N-acetylp-benzoquinone imine reduces excitability in first- and second-order neurons of the pain pathway through actions on KV7 channels (Ray et al, 2019; Pain)

Question 29

what drugs can be used for neuropathic pain

Answer 29

Neuropathic pain has very different treatment options from nociceptive pain.

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

1. Antiepileptic drugs
   Carbamazepine, phenytoin
   (sodium channel blockers)
   gabapentin, pregabalin
   (via effects on calcium channels)
2. Tricyclic antidepressants
   Duloxetine (selective serotonin- and norepinephrine-reuptake inhibitor) and imipramine/amitriptyline (tricyclic antidepressants) effective in conditions such as in diabetic neuropathy
3. Ketamine
   Analgesic (due to block of NMDA receptors)
4. Lidocaine or bupivacaine
   Local anaesthetics which block sodium channels (= nerve block) when injected close to a sensory nerve (also effective epidurally)
5. Ziconotide
   First of new generation calcium channel blockers; administered intrathecal infusion (spinally) to treat neuropathic pain
6. Cannabinoid agonists
   Sativex (mixture of 2 cannabis extracts THC/CBD) licenced in UK to treat pain in multiple sclerosis patients. Mechanism of action not fully known but THC is a cannabinoid receptor agonist.
7. Botulinum toxin
   Analgesic effect by reducing muscular hyperactivity

Question 30

explain the summary drugs of neuropathic pain

Answer 30

• Tricyclic antidepressant- Amitriptyline
  -Serotonin-noradrenaline - Reuptake inhibitors- Duloxetine
  -Voltage-gated calcium channel- alpha2-delta subunit ligands- Gabapentin, pregabalin

not effective/ tolerated?
Offer one of the 3 remaining drugs

Consider Tramadol- (related to morphine)
Consider Capsaicin cream- For localized neuropathic pain

Question 31

non pharmacological and pharmacological Management of Chronic Primary Pain

Answer 31

Chronic primary pain has no clear underlying condition

Non-pharmacological management

Exercise programs
Psychological therapies
Acupuncture
No Tens of Ultrasound

Pharmacological management

Antidepressants

Do not initiate:
Antiepileptic drugs
Antipsychotic drugs
Ketamine
Local anesthetic
NSAIDs
Opioids
Paracetamol

Question 32

what are opioids and their use?

Answer 32

highly effective analgesic
morphine-like drugs, act spinally and supra-spinally to produce analgesia in moderate to severe pain (post-operative, cancer pain

morphine - (agonist)
naloxone - (antgonist)
pethidine - (agonist)
Methadone- (agonist)

Question 33

what are the receptors

Answer 33

M receptor
S rece
k
orl - 1

Question 34

Opioid-induced analgesia

Answer 34

Endogenous opioids bind to presynaptic opioid receptor

Glutamate and other excitatory neurotransmitters (Substance P) are released to continue the pain signal to the brain

Postsynaptic action: to reduce the excitability of dorsal horn
neurons.

Supra-spinal action:
Opioid action at m (d and k) receptors enhances descending inhibitory pathway in brain stem/midbrain involving NA and 5-HT release (by blocking GABA inhibition)

Spinal action:
Activate pre-synaptic m > d receptors to reduce transmitter release

Question 35

Clinical uses of opioid agonists

Answer 35

All act at m 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

Differ only in potency and pharmacokinetics:

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

Fentanyl, alfentanil, sufentanil and remifentanil: very potent, short-duration, often used as a transdermal patch

Oxycodone: used primarily for control of pain in palliative care.

Pethidine: used during labour (due to lack of effect on uterine contraction)

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

Dihydrocodeine: similar efficacy to codeine
- can cause more nausea and vomiting

Diamorphine (heroin): metabolised to morphine, high lipid solubility means rapid action and also higher efficacy (important in the emaciated patient in palliative care)

Tramadol and tapentadol: weak opioids and inhibitors of the noradrenaline uptake/transport system

Partial agonists
Buprenorphine: long duration, can be given sublingually

Question 36

Opioid-induced analgesia: side effects

Answer 36

Euphoria: action on reward pathway in the brain to increase dopamine release (likely related to dependence); however, little euphoria in pain.
For k agonists (pentazocine) side-effects are dysphoria (nightmares, hallucinations) rather than euphoria

Respiratory depression: reduce sensitivity of respiratory centre; most common cause of death from overdose with street use of opioids; treated with naloxone. Side-effects reduced with d and k agonists

Cough suppression (anti-tussive): can be therapeutically useful

Nausea: activate the chemoreceptor trigger zone (which in turn activates the vomiting center) - anti-emetics typically co-prescribed

Constipation: due to maintained contraction of smooth muscle

Question 37

WHO analgesic (pain) ladder

Answer 37

non opiod - aspirin, paracetamol, nsaid
weak opiod - codeine - mild/moderate pain
strong opioda - morphine - moderate to severe pain

Question 38

nice guifline for chronic pain

Answer 38

ch4ck one notes

Question 39

nice guifline for chronic pain

Answer 39

ch4ck one notes