Lisa Johnson, BA, SRS, LATgCertification Review Session2010 ASR Annual Meeting Clearwater Beach, FL

What is Pain?

• Accepted definition:– An unpleasant sensory (noxious) and

emotional experience associated with actual or potential tissue damage

– Anything which would cause more than momentary pain in humans, should be assumed to cause pain in an animal

Definitions

• Agology – the science and study of pain• Allodynia – pain caused by a stimulus that is not normally

painful• Analgesia – the absence, or decrease, of pain in the

presence of a stimulus that would normally be painful• Hyperalgesia – an increased sensitivity to a stimulus that is

normally painful• Nociception – the reception, conduction, and central

nervous processing of nerve signals resulting in the perception of pain

• Somatic pain – pain originating from skin, joints, muscles, and other deep tissues

• Visceral pain – pain originating from the internal organs

Definitions

Noxious stimulus – a stimulus which is actually or potentially damaging to body tissues

Pain threshold – the point at which an individual just begins to feel pain; is relatively consistent among normal individuals

Pain tolerance – the greatest amount of pain that a subject will tolerate; varies greatly among individuals

Radiculalgia – pain along the distribution of one or more sensory nerve roots

Radiculitis – an inflammation of one or more nerve rootsWind-up – a cascade of events resulting from ongoing

stimulation of nociceptors and activation of NMDA receptors; causes hyperalgesia and opioid tolerance

Types of Pain

Physiological Pain• Is a protective

mechanism• Causes avoidance• Little to no tissue injury• Pain stops once the

stimulus is removed

Pathological PainResults from tissue injuryInflammation occurs in the

areaNerve damageRelease of

neurotransmitters with ongoing stimulation of nociceptors

Can lead to hyperalgesiaPersists after the stimulus is

removed

Types of Pain

Acute Pain• Occurs immediately after

a stimulus is received• Severity can vary• Responds well to

treatment• Subsides once stimulus is

removed

Chronic PainPersists well past initial

stimulus (3-6 months)Severity can varyMay or may not respond

well to treatment; may require a “multi-modal” approach

Can result in allodynia, hyperalgesia, and opioid tolerance

Physiology of Pain

• Damaged cells release substances which stimulate nociceptors and inflammation

• Noxious stimuli activate nociceptors, which become sensitized with stimulation, resulting in a lowered stimulation threshold

• A-delta nociceptors are myelinated, conduct impulses rapidly, trigger sensation of first pain (sharp, pricking pain)

• C-fibers are unmyelinated, stimulated by chemicals released in damaged or inflamed tissues, and mediates slow, burning pain

Physiology of Pain

• Sensitized nociceptors cause the release of glutamate and neurokinins from the afferent terminals in the spinal cord

• Activates NMDA (N-methyl-D-asparate) receptors, which are implicated in hypersensitivity (wind-up)

• Afferent neurons in the spinal cord relay the signal to multiple areas in the brain, resulting in the perception of pain

• “Gate control” occurs in the spinal cord, resulting in early inhibition of nociception, allowing escape

Physiology of Pain

• Stimulation of medulary centers result in hyperventilation, increased cardiac output, and increased blood pressure

• Descending neurons act to modulate pain by reducing sensation

• Various neurotransmitters are released: glutamate, norepinephrine, serotonin, gamma-aminobutyric acid (GABA) and endorphins

• Analgesia can be induced by blocking the nociceptive process at one or more points

Physiology of Pain

Pain ≠ NociceptionWhat is the difference?Pain is a product of higher brain center processing of

signals it has received.Nociception refers to the peripheral and central nervous

systems processing information generated by stimulation of nociceptors by noxious stimuli

Nociception can occur in the absence of pain.

Physiology of Pain

There are four distinct processes involved in nociception which can be modulated by analgesics:– Transduction – translation of the noxious stimulus

into electrical activity at the peripheral nociceptor– Transmission – the propagation of nerve

impulses through the nervous system– Modulation – modification of nociceptive

transmission by inhibition of the spinal dorsal horn cells by endorphins

– Perception – the final conscious subjective and emotional experience of pain

Actions of Analgesics on Pain Processes

Transduction:– Can be blocked by local anesthetics by injection either at the site

of injury/incision or intravenously– Can be decreased by use of NSAIDs which decrease the

production of prostaglandins at the site of injuryTransmission:

– Can be prevented by local anesthetics by injection along peripheral nerves, at nerve plexus, or in the epidural or subarachnoid spaces

Modulation:– Can be augmented by injection of local anesthetics or alpha2-

adrenergic agonists; gabapentin may also effect modulationPerception:

– Altered by use of general anesthetics or systemic injection of opioids and/or alpha2-agonists

Actions of Analgesics on Pain Processes

• Pre-emptive analgesia: giving analgesics prior to the noxious stimulus (surgery)– By blocking or inhibiting the nociceptive process

before it begins, hypersensitivity is prevented– May decrease the amount of anesthesia and

post-operative analgesia needed• Multimodal or “balanced” analgesia: using a

combination of analgesics which will impact more than one portion of the nociceptive process– For example: buprenorphine and meloxicam pre-

surgically, lidocaine block used prior to incision, and bupivicaine splash prior to closing incision

Analgesics

• Divided into five main classes based on mode of action– Opioids – Non-steroidal anti-inflammatory drugs – Local anesthetics– Alpha2-adrenoceptor agonists– Miscellaneous drugs

Analgesics - Opioids

• Bind to opioid receptor sites within CNS (mostly µ but also κ)

• Are agonists, partial agonists or mixed agonists-antagonists

• Are controlled substances requiring special licenses and documentation of usage

Opioids

• Agonists – include morphine and fentanyl– Potent opioid analgesics– Have more serious potential side effects than the

mixed agonist/antagonists: respiratory depression, bradycardia, vomiting, constipation

– Can be used in a continuous infusion during anesthesia

– Combined with tranquilizers for neuroleptanalgesic balanced anesthesia

– Can be administered intravenously, intramuscularly, via transdermal patches, and epidurally +/- local anesthetics

– Can be reversed with naloxone

Opioids

• Mixed agonist-antagonist – includes butorphanol– Have agonist or partial agonist activity at one or more

opioid receptors and the ability to antagonize the effects of a full agonist at one or more opioid receptor

– Butorphanol is a mu antagonist and kappa agonist– Butorphanol isn’t routinely used for analgesia

currently due to it’s dosing frequency– Less respiratory depression than full agonists– Can be used post-operatively to reverse the narcosis

of fentanyl while still providing analgesia– Has a “ceiling” effect, at which point increased doses

won’t have any further effect

Opioids

• Partial Agonist – includes buprenorphine– Has both agonist and antagonist activity at the

mu receptor– Can be used to reverse pure mu agonists– Buprenorphine has a prolonged duration of action

(relatively)– Also potential for ceiling effect

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

• NSAIDs are weak organic acids with anti-inflammatory, analgesic, and antipyretic properties

• Inhibit prostaglandin production by inhibiting COX enzymes

• Are either non-selective (inhibits both COX iso-enzymes) or selective for COX-2

• Non-selective NSAIDs have more serious side effects (gastric ulceration and renal toxicity)

• Decreased renal blood flow during anesthesia makes kidneys more susceptible to toxic effects

• Carprofen and meloxicam are COX-2 selective inhibitors which have a reasonable margin of safety when used pre-operatively

Local Anesthetics

• Decrease or prevent Na+ permeability of the membrane of neurons, which stops the transfer of signals along the peripheral nerves

• Prevent central sensitization since the nociceptive signal is blocked

• Classified by duration of action – Lidocaine is short acting with a rapid on-set– Bupivicaine is long acting with a slow on-set– Duration of action can be extended by adding a

vasoconstrictor like epinephrine

Local Anesthetics

Multiple uses and routes of administration• Topical: most are applied to mucous membranes but

some preparations will be absorbed through skin– 0.5% proparacaine is recommended for examining eyes– Lidocaine and benzocaine sprays are used to assist in

intubation (benzocaine has been implicated in methemoglobinemia and should be used sparingly and with caution)

– Xylocaine jell can be used to lubricate endotracheal tubes and urinary catheters

– EMLA cream contains lidocaine and prilocaine and is used to numb skin

Local Anesthetics

• “Splash”– Can apply to exposed tissues prior to closure and

nerves prior to transection during amputations – “Soaker catheters”

• Infiltration– Multiple intradermal or subcutaneous injections of

local anesthetic along proposed incision line– May contain epinephrine (1:200,000) to increase

effect and duration• Field block

– Used to anesthetize large areas• Intradermal or SQ infiltration followed by injection

deeply enough to infiltrate nerves

Local Anesthetics

• Regional blocks (nerve blocks)– Injection into the connective tissue

surrounding a nerve– Can produce loss of sensation and/or

paralysis in the region supplied by the nerve– Requires smaller volumes than field blocks,

reducing the risk of toxicity

Local Anesthetics

• Epidurals– Administered alone or in combination with

other analgesics– If combined, smaller doses can be used,

decreasing risks of adverse effects– Can cause motor deficits at higher doses

Alpha2-Adrenergic Agonists

• Stimulation of the alpha2 – adrenoceptors result in sedation, muscle relaxation, and analgesia

• Can be reversed with alpha2-adrenergic antagonists such as yohimbine and atipamezole

• Includes xylazine, medetomidine, and detomidine

Miscellaneous Analgesics

• Tramadol– Synthetic opioid agonist which also inhibits serotonin and

norepiniphrine re-uptake in the spinal cord– The main metabolite has moderate opioid activity

• Ketamine– NMDA antagonist– Used as a CRI during surgery at sub-anesthetic doses, it

reduces MAC and can help prevent hypersensitivity– More effective treating somatic pain than visceral pain– Can be administered via epidural injection

• Gabapentin– Analogue of naturally occurring neurotransmitter GABA– Believed to increase production of GABA

• Part of endogenous inhibition of nociception – Used to treat nerve pain

Pain Assessment

In order to adequately relieve pain, you need to be able to assess the presence of pain to know if your analgesic regimen is working

Need to be familiar with the species/strain you are working with to be able to recognize normal vs. abnormal behavior

Signs of pain will vary not only between various species, but between strains and individuals within a species

There is no single sign which will always indicate a specific amount of pain universally

Pain Assessment – Signs of Pain

LethargyAvoidanceBiting/licking at injured

area“Worried” expressionVocalizationDisuse of limbAggressionHunched posture“Writhing”

Abnormal postureRuffled coatDecreased food/water

consumption Decreased eliminationListlessnessHiding“Inwardly” focusedFailure to make a nestDisinterest in

environment

Pain Assessment

• Physiological changes can occur:– Increased heart rate– Increased blood pressure– Dilation of pupils– Heat in the effected area– Changes in respiration– Increased cortisol levels– Porphyrin staining around the eyes of rodents

Pain Assessment – Analog Scales

• Establish parameters to score as an indicator of pain, determine what score will indicate insufficient analgesia, and have a rescue plan

• Needs to be species specific• If dealing with a socialized species, can be

used in conjunction with physiological parameters such as heart rate, respiratory rate, and/or blood pressure

Pain Assessment – Analog Scales

So What Do I Need To Know?

• Definitions• Types of pain• Pain pathway• Types of analgesics and their action• Pain assessment

References

• Thurmon JC, Tranquilli WI, Benson GJ, eds. Lumb and Jones’ Veterinary Anesthesia, 3rd edition, Williams & Wilkins, Baltimore. 1996

• NRC, Recognition and Alleviation of Pain in Laboratory Animals, The National Academies Press, Washington, DC. 2009

• Flecknell PA and Waterman-Pearson A. Pain Management in Animals, WB Saunders, London, 2000

• Flecknell PA, Laboratory Animal Anaesthesia, 3rd edition, Academic Press, Boston, 2009