1. Pain and Analgesia Dr Anne Jackson
School of Pharmacy and Biomolecular Sciences
University of Brighton

2. Pain and Analgesia Two themes:
Pain, opioid analgesics and endogenous mechanisms
Psychological aspects of pain and analgesia

3. Pain & Analgesia
Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.
(The International Association for the Study of Pain)

4. SUBJECTIVE experience
Pain & Analgesia
Pain
The Dimensions of Pain
Sensory Dimensions – quality (burning, stabbing etc) & location
Affective Dimensions – unpleasantness, distress, anxiety & depression
Cognitive Dimension – distraction, suggestion
SUBJECTIVE experience

5. Broad Classification of Pain
Type of Pain
Duration
Characteristics
Adaptive?
acute
seconds
eg, contact with hot surface
high – prevents or reduces damage
subchronic
hours to days
resolves on recovery – eg, inflamed wound
protective
chronic or clinical
months to years
exceeds resolution of damage – often profound psychological components
none - maladaptive
Pain is not a unitary phenomenon …
chronic pain needs to be treated

6. Basic Pain Pathways spinal cord brain noxious stimulus
descending inhibition of pain

7. proprioception (motion & posture)
Pain Perception
Sensory information about the world input from periphery as different modalities
touch
proprioception (motion & posture)
temperature
nociception (pain)
nociception is a distinct modality – not just extreme version of other modalities
There are specialised receptors for different modalities.

8. Periphery - nociceptors
hair
epidermis
dermis
free nerve endings
Nociceptors are free nerve endings located in the epidermis. They are sensitive to noxious or destructive stimuli.
present in most bodily tissues – absent from the brain

9. Periphery - nociceptors
mechanical
thermal
polymodal – intense mechanical, thermal
chemicals released on tissue damage (histamine, PGs)
damage induced by chemical release can lead to a sensitized state called hyperalgesia (increase in basal pain sensitivity)

10. Nociceptors
cell bodies located in dorsal root ganglia (or trigeminal ganglia) of the spinal cord
axons extend in two directions – to the periphery & to the spinal cord

11. Afferent neurones from peripheral nociceptors to spinal cord, known as
first order neurones or primary afferent fibres
Aδ (delta) fibres
fast, myelinated, carry information about sharp, well localised pain
conduct impulses at the rate of 20 metres per second
C fibres
slow, unmyelinated, dull aching pain, diffuse localisation
conduct impulses at the rate of 1 metre per second
When nociceptors are activated, information is transmitted to the spinal cord via primary afferent neurones. This occurs via two main types of neurone – the Adelta fibres and the C-fibres.
Fast, myelinated A delta fibers carry sharp, well-localized pain from the surface.
When you touch a hot plate, the first percept is a sharp pain that comes almost immediately.
This message tells your brain to take emergency measures (withdrawal).
Slow, unmyelinated C fibers carry pain from deep within the tissues. The pain is felt as a dull ache which is hard to localize.

12. neurotransmitter is Substance P
primary afferent fibres send information to the dorsal horn of the spinal cord
second order neurons cross over & ascend to the brain: spino-thalamic tract
neurotransmitter is Substance P
primary afferent fibres synapse with second order neurones in the substantia gelatinosa
Primary afferent nociceptors enter the spinal cord via the dorsal root and then synapse with
second order neurons in the dorsal horn of the spinal cord gray matter. Nociceptive neurons then
cross to the contralateral side and ascend predominantly in the spino-thalamic tract.

13. brain is responsible for perception of pain
Brain Sites
ascending second order neurones transfer information to the thalamus & cortex
brain is responsible for perception of pain

14. trigemino – thalamic tract
information about noxious stimulation from the face follows a slightly different route:
trigemino – thalamic tract

15. Gate Control Theory of Pain
Dorsal Horn
area where pain can be modulated
Gate Control Theory of Pain
explains how pain can be reduced by non-painful stimuli
eg – bang elbow – non-painful stimulus (rubbing) masks pain

16. Gate control – Melzak & Wall, 1965
spino-thalamic tract
nociceptors

17. Gate control – Melzak & Wall, 1965
spino-thalamic tract
nociceptors
mechanoreceptors

18. Gate control – Melzak & Wall, 1965
nociceptors
mechanoreceptors
The gate control theory of pain was first proposed by Melzack & Wall in Within the substantia gelatinosa interneurones can modulate activity of the nociceptors. The interneurones can be modulated by input from mechanoreceptors. This causes the release of a neurotransmitter peptide called enkephalin which inhibits the activity of the nociceptors and therefore reduces pain perception.
endogenous opioid neurotransmitter –
enkephalin

19. substantia gelatinosa
Gate Control of Pain
substantia gelatinosa
brain
peripheral modulation – mechanical stimulus
painful stimulus ✗

20. substantia gelatinosa
Gate Control of Pain
substantia gelatinosa
brain
painful stimulus
central modulation – emotions, distraction etc ✗

21. substantia gelatinosa
Gate Control of Pain
substantia gelatinosa
brain
painful stimulus
best known painkiller – morphine ✗

22. Opioids Used to Treat Pain
OPIUM POPPY
papaver somniferum
morphine
codeine
alkaloids, extracted from juices
since 4000 BC – ‘plant of joy’

23. Opioids Used to Treat Pain
heroin
diacetylmorphine
made from morphine that has been extracted from the opium poppy
heroin is metabolised to morphine in the body
morphine
heroin

24. Morphine - General Properties
CNS properties - useful
analgesia (an- ‘without’, algesia- ‘pain’)
good analgesic – but less effective for neuropathic pain (pain associated with nerves)
drowsiness
anti – tussive (cough suppressant)
euphorigenic – helps with pain (but a reason for abuse)

25. Morphine - General Properties
other CNS properties – not useful
pruritis (itching skin; depends on route of administration)
skin flushing
hypothermia
miosis (pupillary constriction) - can be a marker of opioid ingestion
miosis mediated by opioid receptors in the oculomotor nucleus of the medulla

26. Morphine - General Properties
other CNS properties – also not useful
nausea & emesis
mediated by opioid receptors in the area postrema of the medulla
can be treated with 5-HT3 – receptor antagonists (eg, ondansetron)

27. Morphine - General Properties
other CNS properties – most serious side effect
respiratory depression
mediated by opioid receptors in the medulla

28. Peripheral side effects of morphine
GI tract
constipation – tolerance does not develop
antagonists that do not cross BBB could treat this side effect

29. Pain killers similar to morphine
codeine (methylmorphine)
less potent than morphine
usually for mild pain & as anti – tussive
fentanyl (extremely potent)
can be used transdermally
useful if oral administration difficult
fentanyl

30. How does morphine produce analgesia?
spinal cord
brain
noxious stimulus
descending inhibition of pain
inhibiting nociceptive information transfer in the dorsal horn
activation of descending inhibition 1 2

31. Descending Inhibition of Pain
important areas in descending control of pain
periaqueductal gray (PAG)
raphé nucleus
neurones originating from these areas can induce stimulation of interneurons (enkephalin) in the dorsal horn

32. spinal cord inhibition
-receptor agonists also act directly at the level of the spinal cord where endogenous peptides act on  - receptors
Morphine and other mu-receptor agonists also work at the level of the spinal cord. Mu-receptors located in area where endogenous opioids act.
spinal cord inhibition

33. Complications of Opioid Analgesics
morphine, heroin, codeine and fentanyl are  (mu) opioid-receptor agonists
both the therapeutic and the side effects of morphine are mediated by  opioid-receptors
small ‘therapeutic window’ – therapeutic dose is close to the dose that produces serious side effects (respiratory depression)

34. Morphine/Heroin Poisoning (Overdose)
deaths occur due to respiratory depression
clinical overdosage
low BP / shock - delayed absorption
accidental ‘overdose’ in addicts
mixed poisonings in addicts
alcohol or benzodiazepines

35. Morphine/Heroin Poisoning (Overdose)
symptom triad
coma
pinpoint pupils
low respiration rate
in addicts, needle marks can support diagnosis of poisoning
treatment - naloxone (short-acting antagonist acts at mu receptors)
small, i.v. doses - repeat until respiratory depression reversed – care not to precipitate withdrawal if patient is a heroin addict

36. Complications of Opioid Analgesics
two further important complications
tolerance
dependence (later when substance abuse is covered)

37. Tolerance
defined as
the need for increasingly higher doses of drug to achieve the desired effect

38. Tolerance Pharmacologically defined as follows: response
The dose-response curve shifts to the right
The maximum drug effect does not change
acute (single administration)
chronic (continuous administration)
dose
response
max

39. Tolerance dispositional pharmacodynamic dispositional
results from changes in the pharmacokinetics of a drug
leads to reduced concentrations of drug
this usually means a change in rate of metabolism

40. Tolerance dispositional pharmacodynamic pharmacodynamic
‘behavioural tolerance’
effect reduced but concentrations of drug stay same
adaptation has occurred, learning involved

41. Tolerance
tolerance does not develop uniformly to all the effects of a drug
opioids
tolerance will eventually develop to most of their actions (except anti-diarrheal)
mostly pharmacodynamic tolerance (learned, adaptive) and involve classical conditioning

42. Classical (Pavlovian) Conditioning

43. Tolerance to Analgesia
compensatory responses increase with chronic use & become associated with environmental cues (conditioning)
person experiences compensatory response following initial drug effect
eventually, environmental cues alone can trigger compensatory responses  tolerance (need to take more drug)
analgesia
hyperalgesia

44. Summary classification of pain - acute & chronic1
basic pathways - dorsal horn; substantia gelatinosa; spino-thalamic tract; thalamus & cortex 2
inhibition of pain; gate control; descending mechanisms 3
basic properties of opioid analgesics, opioid poisoning & respiratory depression 4
how tolerance develops to opioid analgesia through classical conditioning 5

45. Next … Pain, opioid analgesics and endogenous mechanisms
Psychological aspects of pain and analgesia