Pharmacologic management of pain in the equine patient (Proceedings)

What is pain?

• "an unpleasant sensory and emotional experience associated with actual or potential tissue damage" (International Association for the Study of Pain)

How is pain evaluated in the equine patient?

• Very Difficult!!!!

• Based mostly on subjective evaluation

• May not be evident until severe

o Example of signs of pain: depression, agitation, anorexia, tachycardia, tachypnea, lameness, colic

Pathway of pain

• First order neurons

o Two types of pain receptors (nociceptors):

• Type Aδ myelinated nerve fibers = first, sharp pain

• Type C non-myelinated nerve fibers = slow, burning pain

• Second order neurons

o Dorsal horn of grey matter

o "Gated"

• Excitatory

• Inhibitory

• Spinothalamic tract

o Major ascending pathway for pain conduction

o Contralateral side

• Ventral white matter

• Third order neurons

o In thalamus

o Project to cortex

What is pain? – There are 2 types:

• Physiologic pain

o Stems from noxious stimuli

o Perception is proportional to intensity of stimuli

o "Protective Pain"

o Stimulates a response

• Pathologic pain

o From tissue damage (e.g. inflammation)

o Perception is greater than stimulus

Goals of pain management

• Reduce the morbidity and mortality in patient.

Methods of pain management

• Drugs – IV, IM, oral

• Epidurals

• Continuous rate infusions

• Transdermal

• Novel approaches

NSAIDS

• Inhibit cyclooxygenases (COX)

• Decrease prostaglandin and thromboxane A2

• Effective as analgesics when inflammatory response is present

• Reduce hypersensitivity to pain (local effects)

• May have some central effects (speculated)

• Phenylbutazone

o 2.2 to 4.4 mg/kg BID

o Cumulative affects by 48 hours post-administration

o Oral absorption highly variable especially in fed animal (2-12 hours for peak), but good total absorption

o Peak concentration 3-4 hours (fasted)

o T ½ = 3 - 7 hours (dose dependent)

o Strong COX-1

• Flunixin meglumine

o 1.1 mg/kg

o Effective for visceral pain

o Rapid onset of action

o Duration of action 6 to 12 hours

o Strong COX-1

• Firocoxib

o Equiox

o Coxib

o Highly selective COX-2 inhibitor

o As safe as phenylbutazone at recommended doses (Doucet MY et al. JAVMA Jan 1 232:1; 91-97, 2008)

o Safer at chronic doses?

o Comparable efficacy to phenylbutazone for horses with osteoarthritis (Doucet MY et al. JAVMA Jan 1 232:1; 91-97, 2008)

• Ketoprofen:

o 2.2 mg/kg SID

o Effective in visceral and musculoskeletal models

o COX1 and COX 2

• Carprofen:

o 0.7 mg/kg BID

o Strong COX-2

o Use in foals due to less GI toxicity

• Meloxicam:

o 0.6 mg/kg IV??? or PO SID ??

o IV – rapid clearance from plasma (two studies)

o Very effective NSAID

o Strong COX-2

o Use in foals?

• Aspirin:

o 17 mg/kg PO EOD

o Anti-thrombotic

• Eltenac:

o 0.5-1.0 mg/kg IV SID

o 1 hour onset, 24 hours analgesia

o No sig GI effects

Alpha 2 agonists

• Provide analgesia by binding to α2 receptors in CNS

• Most potent visceral analgesics

• Sedatives

• Xylazine:

o 1.1 mg/kg

o Duration of action = 20 minutes

• Detomidine:

o 20 – 40 µg/kg

o Duration of action = 45 - 90 minutes

Opioids

• Mechanism of action:

o Agonists and mixed agonists and antagonists that suppress nociceptive cells.

o Inhibition of pain transmission in the dorsal horn of the spinal cord and brain

o Activate µ, k, δ receptors

o µ receptor selective drugs have most effective analgesia

o Cause excitement

• Butorphanol:

o 0.1 – 0.4 mg/kg IV or IM

o 3 minutes until onset after IV administration

o Peak 15 to 30 minutes

o Provides 60 to 90 minutes of analgesia IV and up to 4 hours IM.

o Good for visceral analgesia, especially with alpha 2 agonists

o µ and k receptor actions

• Buprenophine:

o 0.005 mg/kg IM

o 6 to 12 hours of analgesia

o High affinity for µ receptors

o Mixed agonist/antagonist

• Morphine:

o 0.05 – 0.6 mg/kg IM

o Causes significant agitation/excitement

• Fentanyl:

o 100 µg patches

o Blood levels and effectiveness not published in the horse

o 48 hours of analgesia

Epidural

• Indications for epidural

o Procedures involving rectum, vagina, perineum, urethra and bladder

• Obstetric manipulations

• Analgesia of in hind-limbs

• Intraoperative

• Contraindications

o Infection at puncture site

o +/- Sepsis

o Uncorrected hypovolemia

o Anticoagulation therapy

o Anatomic abnormalities

• Anatomy

o Epidural space is within the spinal canal outside the visceral layer of the dura matter.

o Not subarachnoid space (site of CSF collection).

• Where do I go?

o Lumbosacral

• Subarachnoid is easier than epidural

• Fastest and best controlled flank anesthesia

• Need special equipment and aseptic technique

o Caudal

• Simple to do, no special equipment

• Can preserve locomotor function of hindlimb

o Lumbosacral subarachnoid

• Same site as CSF collection

• 1 to 2 cm caudal to a line drawn from the cranial edge of tuber sacrale and dorsal midline

• Need a 17.5 cm 17 g spinal needle

o Caudal epidural

• Palpate Co1-Co2 as the first midline depression caudal to the sacrum

• First movable coccygeal articulation when the tail is raised and lowered

• Technique

• 18 gauge 1.5 in needle

• Enter the center of the space perpendicular to the skin

• May feel popping as interarcuate ligament is penetrated

• "Hanging drop"

• Loss of resistance

• Injects easily, air bubble does not compress

o Epidural catheters

• Indicated for continuous epidural analgesia

• Pelvic fractures, hind limb fractures, septic joints, etc.

• Best for repeat dosing

• 17 gauge Huber point directional needle with stylet

• Catheters can cause localized inflammation and fibrosis

• Complications minimal

• Report of 43 catheterizations (Martin CA et al JAVMA 2003 May 15 1394-98)

o Technical problems with catheter predominate

• Kinking, leakage, obstruction, dislodgement, patient problems, non-response to treatment

• What to use in epidural administration

o Local anesthetics – for desensitization

• Where does this block?

• Desensitized skin in a standing horse will depend on amount used

• Lidocaine, Mepivicaine

o Alpha-2 Agonists

• Less motor effects other than profound sedation

• "patchy" analgesia so best when combined

• Can be reversed

o Opioids

• Morphine, meperidine, butorphanol, methadone, hydromorphone

• Most effective and long-acting analgesics

• No excitatory effects when given epidurally

o Dissociatives

• Ketamine

• Only good for short-term analgesia

• Mechanism – NMDA antagonist

o Drug combinations

• Can act synergistically and prolong analgesia

• May provide better analgesia than one agent alone

• Minimize side effects of individual agents

• Complications of epidural administration

o Hypoventilation

o Bradycardia

o Pruritis

o Upward fixation of the patella

o Sepsis

o Recumbency

Continuous rate infusions

• Provide consistent analgesia

• Via fluid infusion pump or drip rate calculations

• Butorphanol

o Loading Dose 17.8 µg/kg

o Rate = 13 µg/kg/hr

o In celiotomy patients: (Sellon DC et al J Vet Intern Med. 2004 Jul-Aug;18(4):555-63)

• Improved behavior scores

• Decreased weight-loss

• Decreased plasma cortisol levels

• Increase time to first defecation

• Lidocaine

o Sodium-channel blocker

o Mechanism:

• Decreases sympathetic tone

• Provides somatic analgesia

• Anti-inflammatory

o Loading dose 1.3 mg/kg

o Rate = 0.05 mg/kg/min

o Used for pain management and decreasing ileus in humans for decades

o Shown to reduce MAC in anesthetized horses

o Side effects include muscle faciculations, ataxia, collapse

• Ketamine (Fielding CM, et al. Am J Vet Res. 2006 Sep;67(9):1484-90)

o 0.4 – 0.8 mg/kg/hr

o No excitation at this dose

o No analgesic effect

• Has analgesic effects in other species

o Complications

• Mild bradycardia and hypotension

Transdermal

• Fentanyl (Orsini et al. J Vet Pharmacol Ther. 2006 Dec;29(6):539-46)

o 2 to 4 - 10 mg patches for adult horses (Orsini et al. J Vet Pharmacol Ther. 2006 Dec;29(6):539-46; Maxwell et al Eq Vet J 2003; 35(5):484-490)

o Need > 1 ng/ml for analgesia

o Absorption is variable among individual horses (Orsini et al. J Vet Pharmacol Ther. 2006 Dec;29(6):539-46

• Only ⅓ of horses reached analgesic levels

• Site of application dependent (Mills et al. Res Vet Sci; 2007; 82:252-256.

• Less absorption from leg vs. groin or thorax

o Lidocaine

• Not absorbed across equine skin (Bidwell et al.Vet Anes and Analg, 2007; 34:443-446)

Things to consider

• Implantable drug delivery systems (pumps)

• Intravenous regional anesthesia

o Currently used in humans

o Can be continuous infusion