Mechanisms of Pain and Analgesia (DONE)

Question 1

What is pain? (add notes from lecture recording)

Answer 1

Nociception- sensitivity to and awareness of noxious/harmful stimuli
Suffering- cerebral awareness, interpretation and anxiety of pain
Made up of affective, cognitive and sensory components

Question 2

The emotional component of pain

Answer 2

Studies have shown that less pain is felt when a patient is distracted from pain, rather than attending to it, or when they are in a good mood rather than a bad mood

Question 3

Components of pain

Answer 3

Sensory- perception of pain characteristics: intensity, quality, location
Affective- negative emotion: anxiety, fear, unpleasant sensation
Cognitive- interpretation of pain
Behavioural- Coping strategy used to express, avoid or control pain
Physiological- nociceptive and stress response

Question 4

Pain characterisation- intensity

Answer 4

Pain intensity is subjective but can be measured in a variety of ways
Commonly 0-10 with 0 being no pain and 10 the worst you have ever felt
0- no pain
1-3- mild pain (nagging, annoying)
4-6- moderate pain (interferes with daily life)
7-10- severe pain (disabling, unable to perform activities of daily life)
Many other scales available e.g. disease specific, children

Question 5

Pain characterisation- duration

Answer 5

Acute: less than 3-6 months, typically non-traumatic psychologically, defined cause, high intensity
Sub-acute/inflammatory: local inflammatory changes, intensity affected by inflammatory mediator
Chronic malignant: progressive and substantial, peripheral and central sensitisations, often cancer development
Chronic non-malignant: often neuropathic in origin, long term, unrelated to peripheral injury, pathology in pathways, harder to treat and manage

Question 6

Nociceptive pain

Answer 6

Visceral or somatic in origin, can be deep or superficial
Presence of a potentially damaging stimulus
Transient
Withdrawal reflex e.g. post surgery

Question 7

Neuropathic pain overview

Answer 7

Peripheral or central in origin
Results from lesions to or disease of the somatosensory nervous system
Commonly chronic rather than acute
Nerve damage, not tissue

Question 8

Inflammatory pain

Answer 8

From tissue inflammation or hypersensitivity
Associated with tissue damage and inflammation
Promotes healing by preventing contact and movement

Question 9

Consequences of neuropathic pain

Answer 9

Hyperalgesia- increased pain to a mildly noxious stimulus, causes central facilitation and peripheral sensitisation
Allodynia- pain to a non-noxious stimulus
Spontaneous pain- pain without stimulus

Question 10

Referred pain

Answer 10

Upper chest/left arm- myocardial ischaemia
Ice cream headache- vagus nerve
General- phantom limb pain
Right shoulder- liver/gallbladder
Left shoulder- thoracic diaphragm/lung

Question 11

Phantom pain

Answer 11

Pain felt by a majority of amputees (50-80%)
The sensations, including pain, often maps to other areas of the body, related to proximity in cortex
E.g. trigeminal nerve severed- map of face on hand
Pain caused because body has not lost central connection in brain when limb is amputated
Some are helped by mirror therapy- ramachandran

Question 12

How do we feel pain?

Answer 12

Nociception- peripheral activation and release of pain mediators
Primary nociceptors, C and Ad fibres
Pain gating- dorsal horn of the spinal cord
Ascending and descending secondary fibres
Pain perception- the brain (thalamus, limbic and cortical systems)

Question 13

Nociception- pain detection in the periphery

Answer 13

Add notes from lecture recording

Question 14

Pain starts with chemicals

Answer 14

Direct stimulators of pain fibres e.g. bradykinin, histamine, 5-HT
Affects the sensitivity of fibres to other transmitters: prostaglandins (targets of NSAIDs), opioids, TRPV1 channel (neuropathic pain)

Question 15

Pain from the nociceptor to the spinal cord

Answer 15

Ad fibres release glutamate (excitatory, over stimulating changes the way nerves fire, involved in learning pathway)
C fibres release substance P, neurokinin A and calcitonin gene-related peptide (activating ascending fibres)

Question 16

Gate control theory- pain control at spinal cord

Answer 16

Inhibitory neurons in spinal cord synapse prevent pain signals from going up ascending fibres
Pain stimulus blocks anything that may inhibit signal i.e. inhibitory neurons
Rubbing skin causes more interference at synapse, blocking more pain e.g. TENS machines

Question 17

Central pain pathways: descending control of pain

Answer 17

Dorsal horn of spinal cord sends message to brain
Amygdala, somatic sensory cortex and hypothalamus influence pain that goes back down spinal cord
Midbrain periaqueductal grey stimulates lots of systems, including Raphe nuclei (production of 5-HT)
Also affects area that produces noradrenaline

Question 18

Descending pathways

Answer 18

Periaqueductal grey receive input from different brain areas- hypothalamus, somatosensory cortex, amygdala
Acts as gatekeeper
Consequences are that brain can influence emotional component of pain

Question 19

How do we treat pain?

Answer 19

Nociception- use NSAIDs to reduce prostaglandin activity
Pain gating- use opiates to target receptors, afferent C fibres in dorsal horn and areas of the brain
Pain perception- use opiates, improve mood through midbrain and forebrain activity, control pain circuitry through PAG and LC

Question 20

Endogenous peptides are differentially distributed

Answer 20

Dynorphins and enkephalins- widely distributed in CNS and found in areas which control:
The perception of pain
Modulation of affective behaviour
Modulation of motor control
Regulation of ANS
Neuroendocrine function

Question 21

Three types of opioid receptors

Answer 21

Mu receptors- targeted by met/leu encephalin, B-endorphin
Kappa receptors- targeted by dynorphins
Delta receptors- targeted by met/leu encephalin, B-endorphin

Question 22

Opiate receptors mediate different effects

Answer 22

Most widely used analgesics act on all receptors so get all effects and side effects, do not have control of selectivity

Question 23

Side effects how opioids relate to receptor distribution

Answer 23

Mu receptors occur in the hypothalamus, cough centre of medulla, chemo-trigger zone and respiratory centre
Limbic system: most receptors found in amygdala, probably do not exert analgesic action, may influence emotional behaviour
Peripherally: gut (motility) and cardiovascular (peripheral vasodilatation, reduced resistance, inhibition of baroreceptor reflexes)

Question 24

3 types of opiates

Answer 24

Full mu agonist- naturally occurring e.g. morphine, codeine; synthetic e.g. diamorphine, pethidine
Partial agonists- nalorphine, pentazocine, buprenorphine, meptazinol
Antagonists- naloxone, naltrexone

Question 25

Opium

Answer 25

Used as a soporofic/hypnotic/analgesic for years
Laudanum- tincture of opium, main active is morphine, 1803
1853- invention of hypodermic syringe and needle
1938- invention of pethidine

Question 26

Morphine

Answer 26

Metabolised quickly by uridine diphospho-glucuronic acid/microsomal UDP glucuonyl transferase
Morphine-3-glucuronide: major, inactive metabolite
Morphine-6-glucuronide: minor, active metabolite

Question 27

Diamorphine

Answer 27

Semi-synthetic, synthesised from morphine
Withdrawal after as little as 3 days
Controlled under schedule 1 and 4
Twice as potent as morphine
Quicker acting than morphine- injection avoids first pass metabolism, more lipophilic therefore more gets to the brain faster

Question 28

Pharmacological effects of morphine

Answer 28

Good: anti-nociceptive at spinal and supra-spinal sites, mood elevating, anxiolytic in forebrain, hypnogesic, antitussive
Bad: respiratory depressant, nauseant and emetic, anti-homeostatic, pharmacological tolerance and physical dependence

Question 29

Common side effects

Answer 29

Constipation- make sure they have laxative
Dizziness, dry mouth, nausea and vomiting
Confusion, oedema, respiratory depression, sweating etc

Question 30

When not to give opioids/ cautionary

Answer 30

Avoid with: acute respiratory depression, raised intracranial pressure, head injury
Hepatic impairment- may precipitate coma
Renal impairment- increased and prolonged effects, use with care
Pregnancy- use of pethidine in labour

Question 31

Critical interactions with opioids

Answer 31

MAO inhibitors: absolute contraindication, high incidence of hyperpyrexic coma
Tricyclic antidepressants/antipsychotic drugs: increased sedation, variable effects on respiration, enhanced pain effect
Sedative hypnotics: increased CNS depression, esp. respiratory

Question 32

Problems with opioid use for chronic pain

Answer 32

Tolerance
Dependence- treated as drug addicts, doctor's responsibility as much as the patients
Expensive and inefficient
Not treating the pain or source
Medical- endocrine, immune system

Question 33

Opiate tolerance- PK

Answer 33

PK
May occur after 10-18 days treatment
Avoid confusion with greater opiate need because of disease progression
May be related to enzyme induction/more rapid production of M3G

Question 34

Opiate tolerance- PD

Answer 34

PD
Changes in receptor density and or release of neurotransmitter
Underlying mechanism linked to up-regulation of adenylyl cyclase
Down-regulation of mRNA not significant

Question 35

Opiate dependence and pain

Answer 35

Opiate addiction fears have influenced its prescription over the years
Addiction following acute treatment unlikely but depends on dose and use and withdrawal symptoms can occur
Typically people under self medicate on a morphine pump in hospital
Physical and psychological dependence can develop when using opiates to treat chronic pain

Question 36

Treating a narcotics overdose

Answer 36

Critical aspect of overdose is respiratory depression
Naloxone very rapid, very effective but precipitates sudden and violent withdrawal
May increase dependent state
Short half life therefore repeated administrations required or relapse will occur
Neutral antagonists e.g. 6b-naltrexol cross BBB and may manage overdose better

Question 37

Opioid hyperalgesia

Answer 37

Opioids elicit paradoxical increase in pain in animals and humans
In humans- hyperalgesia or allodynia noted in different area to original pain
Methadone maintenance patients susceptible
May normally be masked by concurrent analgesia actions
Mechanisms unknown