improving analgesia: dose determination of ketorolac ...€¦ · 2017-09-12 · dubin ae &...

Improving Analgesia: dose determination of ketorolac tromethamine in horsesSHANNON GRADY, PHARMD, FSVHPVETERINARY CLINICAL PHARMACY RESIDENTPURDUE UNIVERSITY VETERINARY TEACHING HOSPITAL

Outline Pathophysiology of pain and inflammation

Review of analgesic agents used in veterinary medicine

Use of ketorolac tromethamine in human and veterinary medicine

Current research in equine medicine and future studies

Learning Objectives Identify drug targets within the arachidonic acid cascade.

Describe the significance of non-steroidal anti-inflammatory drugs in the pain management of veterinary patients.

Describe the use of ketorolac tromethamine in human medicine and how its use can be translated to veterinary medicine.

Disclosures I have no actual or potential conflict of interest in relation to this

presentation.

I will be discussing off-label uses for the following medications:◦ Ketorolac tromethamine

Nociceptive Pain Neuropathic vs. nociceptive vs. inflammatory

Dubin AE & Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest . 2010;120(11):3760-3772


Caused by noxious stimuli◦ Chemical, thermal, mechanical◦ Pressures and temperatures large enough to

cause tissue damage



Caused by noxious stimuli◦ Chemical, thermal, mechanical◦ Pressures and temperatures large enough to

cause tissue damage

Chemical mediators bind to nociceptors

Signal sent to dorsal horn of spinal cord

Transmitted to brain where pain is perceived

Reaction and inflammatory pain


Inflammatory Pain Tissue Damage◦ Inflammatory response

◦ Protective and healing mechanism◦ Acute vs. chronic pain

◦ Drug targets

Zhang J & An J. Cytokines, Inflammation and Pain. Int Anesthesiol Clin. 2007; 45(2): 27-37

Pain Management in Veterinary Medicine Local anesthetics◦ Lidocaine, mepivacaine

Alpha-2 adrenergic agonists◦ Dexmedetomidine, detomidine

Corticosteroids◦ Prednisone, prednisolone

Opioids◦ Fentanyl, morphine, hydromorphone, oxymorphone

Non-steroidal anti-inflammatory drugs (NSAIDs)

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Mechanism of action◦ Inhibition of cyclooxygenase enzymes (COX-1 and COX-2)◦ Prevents formation of prostaglandins

Why NSAIDs?◦ Non-narcotic (opioids)

◦ Not controlled by DEA◦ Fewer, less severe adverse effects

◦ Analgesic and anti-inflammatory properties

Non-selective:

Carprofen (Rimadyl®)

Meloxicam (Metacam®)

Etodolac (EtoGesic®)

Flunixin (Banamine®)

Phenylbutazone

Ketoprofen (Ketofen®)

COX-2 selective:

Deracoxib (Deramaxx®)

Robenacoxib (Onsior®)

Firocoxib (Previcox®, Equioxx®)

Arachidonic Acid CascadeCELL

MEMBRANE

PhospholipidsPhospholipase Arachidonic

Acid

Riviere JE & Papich MG. Veterinary Pharmacology and Therapeutics, 9 th Edition. Ames, IA: Wiley-Blackwell, 2009.


MEMBRANE


Acid


Leukotrienes

Thromboxane A2

Prostaglandins (PGE2)

Cyclooxygenase-1 & 2

Lipoxygenase

Cyclooxygenase-1

Prostaglandins Primary mediators of inflammatory pain◦ PGE2

Nociceptors contain EP4 receptors

Drug target

PGE2

EP4 Receptor

Dorsal Root Ganglion



MEMBRANE


Acid


Leukotrienes

Thromboxane A2

Prostaglandins (PGE2)

Cyclooxygenase-1 & 2

Lipoxygenase

Cyclooxygenase-1

Drug Target

Novel NSAID: ketorolac tromethamine 1970s

Extremely potent anti-inflammatory and analgesic◦ Rats: 500-800x more potent than aspirin

FDA-approved in humans◦ Short-term management of moderate-severe pain in

patients requiring opioid-level analgesia◦ Usually post-operative pain

“Opioid-sparing”

Rooks, et al. The pharmacologic activity of ketorolac tromethamine. Pharmacotherapy . 1990;10*6 Pt 2): 30S-32S.

Ketorolac: human studies 60 patient undergoing elective hysterectomy

Continuous-rate infusion of ketorolac or placebo◦ Total daily dosage: 120 mg◦ 0.6 – 1.3 mg/kg/day

Outcomes:◦ Frequency of supplementary analgesia use

◦ Morphine via patient-controlled analgesia (PCA)

◦ Pain score at 24 hours post-procedure

Results:◦ Morphine consumption significantly lower in ketorolac group than placebo group (21.5% less)◦ Patient-reported pain significantly lower in ketorolac group after 24 hours

Blackburn A et al. Balanced Analgesia with Intravenous Ketorolac and Patient-Controlled Morphine Following Lower Abdominal Surgery. J Clin Anesth. 1995;7:103-108

Ketorolac: human studies 191 human patients undergoing major abdominal surgeries

Maximum ketorolac dosage: 150 mg per 24 hours◦ 0.8 to 1.7 mg/kg/day

Results:◦ Both ketorolac groups required less total morphine◦ No differences in adverse events between groups

All received supplemental morphine as

needed

O’Hara DA et al. Evaluation of the Safety and Efficacy of Ketorolac versus Morphine by Patient-Controlled Analgesia for Postoperative Pain. Pharmacotherapy . 1997;17(5):891-899.

Pain Management in Equine Medicine NSAIDs◦ Flunixin (Banamine®)◦ Phenylbutazone◦ Ketoprofen (Anafen®)◦ Firocoxib (Equioxx®)

Opioids◦ Butorphanol

Local anesthetics◦ Mepivacaine, Lidocaine

Corticosteroids◦ Dexamethasone

What’s missing?Lack of efficacy in certain clinical situations

OsteoarthritisPost-operative musculoskeletal pain (i.e. arthrodesis)LaminitisPleuritis

Ketorolac: equine studies Ferraresi et al, 2014

Pharmacokinetic study in 6 colts undergoing orchiectomy

0.5 mg/kg single IV injection after intubation, approximately 10 minutes prior to surgery◦ Dose derived from previous canine and feline studies

Results:◦ No adverse effects, however:

◦ Did not specify parameters for NSAID◦ No placebo control for comparison

◦ Rapid distribution◦ Short half-life (0.7 hours)

Ferraresi C et al. Pharmacokinetics of IV Ketorolac in Horses Undergoing Orchiectomy. J Equine Vet Sci . 2014;34:870-875.

Ketorolac: equine studies Bianco AW et al, 2015

Randomized, cross-over study of 9 healthy, adult horses

0.5 mg/kg ketorolac given IV, IM and PO

Monitoring of adverse events◦ Changes in behavior, appetite, fecal consistency

Results◦ Rapid absorption after IM and PO administration◦ Bioavailability 71% (IM) and 57% (PO)◦ IV half-life: mean 8.7 hours (range 1.2 – 21.9 hours)

Bianco AW et al. Pharmacokinetics of ketorolac tromethamine in horses after intravenous, intramuscular and oral single-dose administration. J Vet Pharmacol Therap. 2015;39,167-75.

Ketorolac: literature recap Ketorolac is “opioid-sparing”◦ Less opioid needed to control pain in humans◦ Fewer side effects from opioids

Dosage◦ Large dosage range seen in human studies◦ Only 0.5 mg/kg studied in horses◦ Up to 2 mg/kg studied in goats, sheep, calves

Horses◦ Pharmacokinetic profile has been established◦ No studies comparing placebo/control group to assess efficacy or safety◦ No studies comparing ketorolac to other analgesic agents

Pilot Study How does ketorolac compare to other NSAIDs commonly used in horses?

Establish a dose of ketorolac to use in a cross-over study◦ Is ketorolac effective at higher doses than previously studied?◦ Are there any adverse effects seen at higher doses?

Pilot Study Objective: determine appropriate dosage of ketorolac to use in a study comparing ketorolac to other NSAIDs in horses

◦ 0.5, 1 and 2 mg/kg

Efficacy Endpoints Analgesia Heart rateSubjective lameness scoreObjective lameness score

Safety Endpoints Nephrotoxicity Serum creatinineUrine specific gravityProteinuria

Gastrointestinal toxicity Fecal occult blood test

Hematologic toxicity Platelet countWhite blood cell count with differential

Foot Lameness Model Developed by JH Foreman (University of Illinois)

Customized heart bar shoe placed on left front foot◦ Counterbalanced bar shoe on right front foot

At least 1 week of rest in pasture

Screw inserted into screw and tightened at beginning of each trial

Temporary, reversible lameness

Foreman JH & Lawrence LM (1987) Lameness and heart rate elevation in the exercising horse. Proceedings of the Equine Nutrition & Physiology Symposium,10,345.

Foot Lameness Model

Video here

Foot Lameness Model

Evaluation of Foot Pain Heart rate◦ Elevated when mammals are in pain

Lameness evaluation◦ Subjective lameness score (0 to 5)

◦ Assigned by large animal surgeons◦ Equinosis® Lameness Locator Score

◦ Distance measured in millimeters

Timeline of Trials 1. Customized shoes made and placed on horses

2. At least 1 week of rest on pasture to acclimate to shoe

3. Return to VTH for trial

4. Baseline data collected◦ Physical exam, bloodwork, urinalysis, fecal occult blood testing◦ Baseline lameness

5. Trial (4 days)

6. Horses returned to pasture for at least 2 week washout period

7. Returned to VTH for next trial

Timeline of Trials Trial Days:◦ Drug given on day 0 at 8:00am◦ Lameness evaluated throughout the day until horse returned to baseline lameness score

◦ Heart rate, subjective lameness score, objective lameness score◦ t = 30 mins, t = 1h, t = 1.5h, t = 2h, t = 3h, t = 4h, t = 5h, t = 6h, t = 7h, t = 8h, t = 9h, t = 10h, t = 11h, t = 12h

◦ Lameness alleviated (screw removed from shoe) once horse returned to baseline

◦ Bloodwork, urinalysis, FOBT performed every 24 hours after drug given (day 1, day 2, day 3)◦ Physical exams performed every 12 hours

Results Study population from Purdue University Teaching Herd (n = 4)

◦ Horse 1: 14 y/o Thoroughbred mare◦ Horse 2: 14 y/o Thoroughbred mare◦ Horse 3: 6 y/o Thoroughbred gelding◦ Horse 4: 16 y/o Thoroughbred mare

Inclusion criteria◦ Sound (0/5 lameness score)◦ No NSAID administration within the past 2 months◦ Otherwise healthy

Results – Horse 1, Baseline

Video here

Results – Horse 1, Lameness Grade 4

Video here

Results – Horse 1 – 2h after ketorolac

Video here

Results – Lameness Scores


Baseline Peak Effect Percent Improvement = (Difference / Baseline)

Results – Percentage Improvement in Lameness Locator Score

Results – Changes in Serum Creatinine Over Time

Limitations and Lessons Learned Grade 4 lameness translates to different Lameness Locator numbers depending on the horse

Difficulties with customized shoes◦ Broken screws◦ Cracked frog◦ Lost on pasture

Distractions during lameness evaluations in hospital

◦ Horse #3

Disparity between objective and subjective lameness evaluations

Horse #4◦ Grand mal seizure & subsequent euthanasia◦ 7 hours after receiving ketorolac at 0.5 mg/kg◦ Had already reached baseline lameness

◦ Did not lose data

◦ Necropsy unremarkable◦ Likely not attributable to ketorolac

Current Research Ketorolac 2 mg/kg◦ More consistent response in percentage reduction in lameness◦ No adverse effects◦ Doses of other NSAIDs on high end of dosing range

◦ Pleuritis, laminitis, osteoarthritis, post-operative musculoskeletal pain

Same lameness model as pilot study

Same inclusion criteria

Same efficacy and safety parameters

Current Research Randomized Latin Square cross-over design (n = 12 horses)◦ Ketorolac 2 mg/kg◦ Phenylbutazone 4.4 mg/kg◦ Flunixin 1.1 mg/kg◦ NaCl 0.9% (placebo)

Dosing interval extended to 5 days with every 12 hour doses

Washout period of >2 weeks between trials

Current Research Analgesia vs. anti-inflammatory action◦ Inflammatory marker in cephalic vein blood

◦ Serum Amyloid A, cytokines◦ Baseline, immediately after lameness induction, immediately prior to first dose, 2h, 12h

◦ Thermography◦ Visual representation of inflammation◦ Baseline, immediately after lameness induction, immediately prior to first dose, 2h, 12h

Pharmacokinetic comparison◦ Pharmacokinetics of ketorolac, phenylbutazone, flunixin

◦ 5 min, 2h, 4h, 8h, 12h

Current Research 2 of 4 trials complete

Improvement seen within placebo group◦ Horses become acclimated to screw?

Different surface used for lameness evaluations

◦ Minimize distractions

Horses ◦ Horse 1: 14 y/o Thoroughbred mare◦ Horse 2: 15 y/o Thoroughbred mare◦ Horse 3: 6 y/o Thoroughbred gelding◦ Horse 4: 11 y/o Arabian mare◦ Horse 5: 22 y/o Thoroughbred mare◦ Horse 6: 13 y/o Thoroughbred mare◦ Horse 7 : 16 y/o Thoroughbred mare◦ Horse 8: 6 y/o Mixed Breed mare◦ Horse 9: 15 y/o Standardbred mare◦ Horse 10: 11 y/o Standardbred mare◦ Horse 11: 4 y/o Thoroughbred mare◦ Horse 12: 12 y/o Standardbred gelding

Excluded

Future Research Inflammatory markers◦ Lipopolysaccharide-induced synovitis model

Continuous-rate infusion◦ Common in human medicine◦ Combination with other analgesics

Comparison to commonly used equine opioids◦ Butorphanol, Morphine

Take Home Points The arachidonic acid cascade is a primary drug target for reducing pain in inflammatory diseases

Ketorolac is a potent NSAID that is commonly used in human medicine for pain requiring opioid-level analgesia

Ketorolac appears to be effective in reducing analgesia in horses with experimentally-induced lameness

Ketorolac may have a role in controlling painful inflammatory diseases in horses

Questions? Acknowledgements:◦ Co-Investigators:

◦ Sandra Taylor, DVM, PhD, DACVIM (LA)◦ Timothy Lescun, BVSc, MS◦ Alec Davern, DVM

◦ Statistics:◦ George Moore, DVM, PhD

◦ Others:◦ Wil Gwin, RPh, DICVP◦ Alex Bianco, DVM, MS, DACVIM (LA)◦ John Foreman, DVM, MS, DACVIM (LA)◦ Jeff Ko, DVM, MS, DACVA◦ Molly Cripe-Birt (large animal technician)◦ Jordan Keehn (veterinary technology student)

improving analgesia: dose determination of ketorolac ...€¦ · 2017-09-12 · dubin ae &...

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