Pain, physiology, treatment, Nociceptor, Unpleasant sensory and emotional experience associated with actual or potential tissue damage, Central Sensitization, pathologic pain, physiologic pain, chronic pain, visceral pain, neuropathic pain, Opioids Local Anesthetics Non Steroidal Anti Inflammatory Drugs Alpha 2 adrenergic agonists NMDA Antagonists GABApentin Tramadol

1. PAIN: PHYSIOLOGY AND
TREATMENT

2. Definitions
• Pain
– “Unpleasant sensory and emotional experience
associated with actual or potential tissue
damage or described in terms of such damage”.
• Nociceptor
– is a receptor that is preferentially sensitive to a
noxious (damaging to tissue) stimulus or to a
stimulus that would become noxious if
prolonged.

3. Transduction
Transmission
Modulation
Perception

4. Transduction
• Mechanical, chemical and thermal energy
are converted into electrical
energy/impulses by specialized nerve
endings called “nociceptors”
• Nociceptors
– free nerve endings of primary afferent fibers.
– have high stimulus thresholds for activation.

5. Nociceptors
• A-fiber mechanoheat receptors
-signal “first” pain (sharp, stinging, pricking
sensation), well localized pain, transient, lasts only
as long as the stimulus activates the nociceptors
C-fiber mechanoheat (polymodal) receptors
-mediate “second” or “slow” pain, a diffuse,
persistent sensation that exists past the termination
of an acute painful stimulus.

6. Nociceptors
• Repeated stimulation produces:
– reduction in receptor threshold
– an enhanced magnitude of response.

7. Transmission
• occurs along 2 different types of afferent
nerve fibers:
A-delta fibers
– large diameter
– myelinated
– rapid impulse conduction (6-30 m/sec)
– stimulates immediate reaction

8. Transmission
• C fibers
– small diameter
– unmyelinated
– slow conduction
• (0.5 – 2 m/sec)
– reinforces the immediate
response that is signaled by A-delta fibers

9. Transmission
• Spinothalamic tract
– Most important tract in
transmission of nociceptive
information
• Spinoreticular tract
• Spinohypothalamic tract

10. Perception-Supraspinal
Processing
• Reticular System
• Limbic System
• Thalamus
• Cortex

11. Transduction
Transmission
Modulation
Perception

12. Descending Modulation
• Inhibitory influences at the
cortical and spinal cord levels
• Inhibitory neurotransmitters
include GABA, glycine,
serotonin, dopamine, NE,
endogenous opioids

13. Peripheral Sensitization
• arises as a result of the exposure of
nociceptor to chemical mediators of
inflammation: substance P, hydrogen ions,
norepinephrine, bradydkinin, histamine,
potassium, cytokines, serotonin, nitric oxide
• all of these mediators act together to lower
the response threshold of both the A-delta
and C fibers nociceptors

14. Central Sensitization
• Produced by changes in the membrane
excitability of dorsal horn neurons.
– Increase in receptive field of dorsal horn
neurons (zone of secondary hyperalgesia).
– increased responsiveness to mechanical
stimulation that is normally innocuous
(allodynia).
– Recruitment of non-nociceptive receptors (A-
beta fibers)

15. Types of Pain
• Physiologic pain
– transient stimulus, no tissue damage or
inflammation, neurophysiology associated with
simple stimulus-response model.

16. Types of Pain
• Pathologic pain
– pain that arises in the clinical setting
– involves dynamic changes in the processing of noxious
input at both the peripheral and central levels
– stimulus is not transient
– usually associated with significant tissue inflammation.
– can be associated with damage to nervous tissue
(neuropathic pain).
– recently occurring (acute) or long-lasting (chronic).

17. Acute Post-Operative Pain
• arises from soft tissue trauma or inflammation
• plays a biologically adaptive role by facilitating
tissue repair
– functions:
-hypersensitizes injured area (primary hyperalgesia)
-sensitizes surrounding tissues (secondary
hyperalgesia)
– serves to facilitate avoidance of external stimuli
– doesn’t give license to allow pain to exist untreated

18. Chronic Pain:
• pain that persists beyond the expected time frame
for a given disease, process or injury.
• may be associated with ongoing inflammation
• may be autonomous with no temporal relation to
the inciting cause.
• Maladaptive, offers no biologic advantage
• examples of chronic pain:
– cancer pain
– osteoarthritic pain
– postamputation phantom limb pain

19. Visceral Pain
• nature of pain originating from viscera versus
somatic tissues is significantly different.
• the viscera most sensitive to distention (hollow
organs of GI tract), ischemia (myocardium) and
inflammation (pancreatitis).
• poorly localized.
• referred – pain response is localized to distant
structures

20. Neuropathic Pain
• produced as a consequence of damage to the
nervous system.
• characterized by altered sensory processing of
stimuli
• several manifestations of hypersensitivity:
– persistent burning sensations, partial or focal loss of
sensitivity
• allodynia (an increased responsiveness to
mechanical stimulation that is normally
innocuous).
• may arise from an acute injury discharge in
axotomized afferent fibers.

21. Systemic Response to Pain and
Injury
• increased sympathetic tone
– vasoconstriction
– increased cardiac output through increases in
stroke volume and heart rate
– decreased gastrointestinal and urinary tone
– increased skeletal muscle tone

22. Systemic Response to Pain and
Injury
• hormonal changes
– increased secretion of cortisol, ADH, catecholamines,
renin, angiotensin II, aldosterone
– decreases in insulin and testosterone
• endocrine changes result in a catabolic state:
– hyperglycemia
– increased protein catabolism and lipolysis,
– renal retention of water and sodium,
– increased potassium excretion
– decreased GFR.

23. Stress Response Markers/Pain
Assessment
• heart rate
• respiratory rate
• blood pressure
• posture
• attitude
• food and water intake
• patterns of defecation, urination

24. Stress Response Markers/Pain
Assessment
• Change in activity levels
• Natural behaviors – inquisitive, grooming
• Provoked behavior
• Aggression
• Gait-/posture
• Vocalization
• Appearance of stereotypical behaviors

25. General Approaches to Pain
Management
• minimize debilitating pathologic pain while
maintaining the protective and adaptive
aspects associated with physiologic pain.
• a single drug administered at a standard
dose for different pain syndromes is not an
effective pain management strategy.

26. General Approaches to Pain
Management
• Pre-emptive analgesia
-initiating treatment prior to acute insult helps to
limit the development of peripheral and central
sensitization.

27. General Approaches to Pain
Management
• Multimodal/balanced
analgesia:
– combining analgesic
drugs and techniques
to achieve beneficial
additive or synergistic
analgesic effects.
– can use lower doses,
fewer side effects.

28. General Classes of Analgesic
Drugs
• 1. Opioids
• 2. Local Anesthetics
• 3. Non Steroidal Anti Inflammatory Drugs
• 4. Alpha 2 adrenergic agonists
• 5. NMDA Antagonists
• 6. Others
• GABApentin
• Tramadol

29. OPIOID ANALGESICS

30. USES
• 1. sedation
• 2. analgesia
• a. preoperatively
• b. intraoperatively
• c. postoperatively
• 3. neuroleptanalgesia
• a. in combination with a
tranquilizer/sedative
• b. useful for minor procedures that do not
require general anesthesia

31. Opioid Classification
• Agonists
– Stimulate receptor activity
– Mu agonists
• most common group of opioid agonists used
• Include morphine, meperidine, oxymorphone,
hydromorphone, fentanyl, carfentanil

32. Opioid Classification
• Agonists-Antagonists
– Stimulate activity at some receptors and
antagonize others
– Butorphanol – kappa agonist, mu antagonist

33. Opioid Classification
• Partial Agonists
– Bind to receptor but only produce a partial
effect
• Buprenorphine – partial mu agonist, kappa
antagonist

34. Opioid Classification
• Antagonists
– Primary activity is mu receptor antagonism
• Naloxone
• Naltrexone
• Nalmefene
• Diprenorphine

35. • Classification:
– Traditional:
• μ, κ, δ, ε, σ
– New (?) Classification:
• OP1 (δ), OP2 (κ), OP3 (μ)
Opioid Receptor
Pharmacology

36. Opioid Receptor Pharmacology
• Mu
– Supraspinal, spinal, peripheral analgesia
– Respiratory depression
– Euphoria/Sedation
– Physical dependence
– Bradycardia

37. Opioid Receptor Pharmacology
• Kappa
– Spinal analgesia
– Sedation
– Respiratory depression
• Sigma (opioid receptor?)
– Dysphoria/hallucinations
– Hypertonia
– Respiratory stimulation
– tachycardia

38. Opioid Effects
• Cardiovascular
– Bradycardia – vagally mediated
– Negligible effect on myocardial contractility
– Hypotension due to histamine release
• Seen with morphine, meperidine (particularly when
administered IV)
• Not a problem with synthetic opioids

39. Opioid Effects
• Respiratory
– Decrease in frequency and tidal volume
– Blunts response to carbon dioxide
– Cough suppressant

40. Opioid Effects
• CNS
– Narcosis – sedation, euphoria, hypnosis, analgesia,
excitement, dysphoria
– Medullary depression
• Respiratory center
• Cough center
• Vomiting center (delayed)
– Vomiting center (early)
– Vagus nerve
– Oculomotor nerve (miosis – dog; mydriasis – horse,
cat)

41. Opioid Effects
• Gastrointestinal
– Salivation
– Nausea
– Vomiting
– Nonpropulsive hypermotility
– Defecation

42. Opioid Effects
• Species Specific Effects
– Excitement in horses (u agonists;
agonists/antagonists)
– Excitement in cats (dose related)
– Panting in dogs – resets thermostat
– Sweating in horses

43. Opioid Pharmacology:
Distribution

44. Routes of Administration
• SC, IM, IV
• CRI
• Oral
• Epidural
• Transdermal
• Intra-articular

45. Epidural Catheter

46. Epidural Catheter

47.
Commonly Used Opioids
Mu agonists
DRUG DOSE (MG/KG)
ROUTE
DUR
ATIO
N
COST
(20
KG)
Morphine 0.5 – 1
IM/SC
4-6 0.27
Meperidine 2 –6
IM/SC
1-2 1.47
Fentanyl .004-0.008
IV/IM/SC
1-2 4.80
Oxymorphone 0.05-0.2
IV/IM/SC
4-6 14.00
Hydromorphone 0.1-0.2
IV/IM/SC
4-6 0.76

48.
Commonly Used Opioids
Mixed agonists/antagonists
DRUG DOSE (MG/KG)
ROUTE
DURA
TION
Butorphanol 0.2-0.4
IV/IM/SC
3-4
Buprenorphine 0.01-0.02
IV/IM/SC/PO
8-12

49. Reversal of Opioid Effects
• Naloxone (1 ug/kg diluted in 5-10 ml
normal)
• Butorphanol (0.1-0.2 mg/kg)

50. Which Opioid?
Which Route of Administration?
• Nature of procedure – severity and
expected duration of pain.
• Nature of patient
• Resources

51. Neuroleptanalgesia
• A state of quiescence, altered awareness and
analgesia produced by the administration of an
opioid analgesic and a tranquilizer or sedative
• Indications:
– Minor surgical procedures
– Diagnostic procedures
– Premedication for General Anesthesia
– Induction of General Anesthesia

52. Neuroleptanalgesia
• Clinical Effects
– Narcosis without unconsciousness
– Hyper-responsive to auditory stimuli
– Defecation
– Respiratory depression
– Bradycardia
– Analgesia

53. Neuroleptanalgesia
• Combinations:
Acepromazine
Midazolam
Diazepam
Oxymorphone
Hydromorphone
Butorphanol
Morphine
Buprenorphine
Fentanyl