PAIN: PHYSIOLOGY AND TREATMENT

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.

Transduction

TransmissionModulation

Perception

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.

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.

Nociceptors

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

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

Transmission

• C fibers– small diameter– unmyelinated– slow conduction

• (0.5 – 2 m/sec)

– reinforces the immediate

response that is signaled by A-delta fibers

Transmission

• Spinothalamic tract– Most important tract in

transmission of nociceptive

information

• Spinoreticular tract

• Spinohypothalamic tract

Perception-Supraspinal Processing

• Reticular System

• Limbic System

• Thalamus

• Cortex

Transduction

TransmissionModulation

Perception

Descending Modulation

• Inhibitory influences at the

cortical and spinal cord levels

• Inhibitory neurotransmitters

include GABA, glycine,

serotonin, dopamine, NE,

endogenous opioids

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

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)

Types of Pain

• Physiologic pain– transient stimulus, no tissue damage or

inflammation, neurophysiology associated with simple stimulus-response model.

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).

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

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

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

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.

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

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.

Stress Response Markers/Pain Assessment

• heart rate

• respiratory rate

• blood pressure

• posture

• attitude

• food and water intake

• patterns of defecation, urination

Stress Response Markers/Pain Assessment

• Change in activity levels

• Natural behaviors – inquisitive, grooming

• Provoked behavior

• Aggression

• Gait-/posture

• Vocalization

• Appearance of stereotypical behaviors

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.

General Approaches to Pain Management

• Pre-emptive analgesia-initiating treatment prior to acute insult helps to

limit the development of peripheral and central sensitization.

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.

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

OPIOID ANALGESICS

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

Opioid Classification

• Agonists– Stimulate receptor activity– Mu agonists

• most common group of opioid agonists used

• Include morphine, meperidine, oxymorphone, hydromorphone, fentanyl, carfentanil

Opioid Classification

• Agonists-Antagonists– Stimulate activity at some receptors and

antagonize others– Butorphanol – kappa agonist, mu antagonist

Opioid Classification

• Partial Agonists– Bind to receptor but only produce a partial

effect• Buprenorphine – partial mu agonist, kappa

antagonist

Opioid Classification

• Antagonists– Primary activity is mu receptor antagonism

• Naloxone

• Naltrexone

• Nalmefene

• Diprenorphine

• Classification:– Traditional:

• μ, κ, δ, ε, σ

– New (?) Classification: • OP1 (δ), OP2 (κ), OP3 (μ)

Opioid Receptor Pharmacology

Opioid Receptor Pharmacology

• Mu– Supraspinal, spinal, peripheral analgesia– Respiratory depression– Euphoria/Sedation– Physical dependence– Bradycardia

Opioid Receptor Pharmacology

• Kappa– Spinal analgesia

– Sedation

– Respiratory depression

• Sigma (opioid receptor?)– Dysphoria/hallucinations

– Hypertonia

– Respiratory stimulation

– tachycardia

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

Opioid Effects

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

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)

Opioid Effects

• Gastrointestinal– Salivation– Nausea– Vomiting– Nonpropulsive hypermotility– Defecation

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

Opioid Pharmacology:Distribution

Routes of Administration

• SC, IM, IV

• CRI

• Oral

• Epidural

• Transdermal

• Intra-articular

Epidural Catheter

Epidural Catheter

 Commonly Used Opioids

Mu agonists  

  

DRUG DOSE (MG/KG)

ROUTE

DURATION

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

 Commonly Used Opioids

Mixed agonists/antagonists   

  

DRUG DOSE (MG/KG)

ROUTE

DURATION

Butorphanol 0.2-0.4

IV/IM/SC

3-4

Buprenorphine 0.01-0.02

IV/IM/SC/PO

8-12

Reversal of Opioid Effects

• Naloxone (1 ug/kg diluted in 5-10 ml normal)

• Butorphanol (0.1-0.2 mg/kg)

Which Opioid? Which Route of Administration?

• Nature of procedure – severity and expected duration of pain.

• Nature of patient

• Resources

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

Neuroleptanalgesia

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

Neuroleptanalgesia

• Combinations:

Acepromazine

Midazolam

Diazepam

Oxymorphone

Hydromorphone

Butorphanol

Morphine

Buprenorphine

Fentanyl